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Presented  By 

I^DR.  WILLIAM  J.  Oils g^ 

to  enrich  the  bhraiy  resources 

availaSle  to  holders 

ofthe 

GlES  FELLOWSHIP 

in  Biological  Chemistry 


THE 

DUCTLESS  GLANDULAR 

DISEASES 

F  A  LT  A 


THE 

DUCTLESS  GLANDULAR 
DISEASES 


BY 

WILHELM  FALTA 


TRANSLATED  AND  EDITED  BY 

MILTON  K.  MEYERS,  M.  D. 

NEUROLOGIST    TO    THE    LEBANON    HOSPITAL,    AND    TO   THE   DISPENSARIES    OF    THE 
JEWISH    AND    ST.    AGNES    HOSPITALS,    PHILADELPHIA,    ETC.,    ETC. 


WITH  A  FOREWORD  BY 

ARCHIBALD  E.  GARROD,  M.  D.  (Oxon.) 
F.  R.  C.  P.  (London),  F.  R.  S. 

PHYSICIAN   TO   ST.    BARTHOLOMEW'S    HOSPITAL,    LONDON 


SECOND  EDITION 


WITH  101  ILLUSTRATIONS  IN  THE  TEXT 


PHILADELPHIA 

P.   BLAKISTON'S   SON   &   CO. 

1012   WALNUT   STREET 


Copyright,  1916,  by  P.  Blakiston's  Sox  &  Co. 


THK    ilAPLE     PHKSS     yORK    PA 


DEDICATED 

TO  MY 

CLINICAL  MASTERS 

W.  HIS,  FR.  V.  MULLER 

AND 

C.  V.  NOORDEN 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/ductlessglandulaOOfalt 


PREFACE 

The  considerable  impetus  that  has  been  given  to  the  study  of  the  internal 
secretion  in  the  last  two  decades  quite  justifies  the  experiment  of  publishing ^ 
the  diseases  of  the  ductless  glands  connectedly.     The  experimental  physiol- 
ogy and  pathology  has  been  dealt  with  in  exhaustive  fashion  in  the  excellent 
work  of  A .  Biedl. 

The  present  volume  is  concerned  with  the  clinical  aspects  of  the  diseases 
of  the  ductless  glands.  Of  the  results  of  experimental  pathology  I  have  set 
forth  only  as  much  as  seemed  to  me  necessary  for  the  explanation  of  the  clin- 
ical manifestations.  For  the  rest  of  these  results  the  reader  is  referred  to 
the  work  of  Biedl. 

In  most  of  the  chapters  I  have  tried  to  describe  the  clinical  symptomatol- 
ogy on  the  basis  of  my  own  observations,  such  as  I  had  occasion  to  make, 
for  the  most  part,  at  the  first  medical  clinic  in  Vienna. 

Prof.  Dr.  L.  von  Frankl-H ockwart  and  Privat-Docent  Dr.  R.  Stern  I  thank 
cordially  for  the  revision  of  the  neurological  part,  Prof.  Dr.  Stoerck  for  the 
revision  of  the  pathologico-anatomical  part,  and  the  latter  also  for  numerous 
microscopical  preparations.  The  X-ray  examinations,  when  not  especially 
credited,  were  by  Dr.  G.  Schwarz,  director  of  the  Roentgen  division  of  the 
first  medical  clinic.  I  thank  Assistant  Dr.  S.  Bernheim  for  aid  in  the  work- 
ing-through of  numerous  experimental  questions.  Finally  I  am  indebted  to 
my  publishers,  the  firm  of  Julius  Springer ^  for  their  assistance  in  the  fitting- 
out  of  the  book. 

W.  Falta. 
Vienna. 


EDITOR'S  PREFACE 

The  aim  and  effort  of  the  American  editor  has  been  to  furnish,  not  merely 
a  faithful  rendering  of  the  German  text,  but  also  a  rounding  out  of  the  sub- 
ject by  the  consideration  of  recent  American  and  English  views.  To  this 
end  he  has  consulted  a  wealth  of  material,  comprising  some  hundreds  of 
references  and  numerous  original  articles,  from  which  it  is  quite  apparent 
that  many  of  the  investigators  have  been  concerned  with  the  purely  scien- 
tific or  abstruse,  rather  than  with  the  clinical  aspects  of  the  subject.  While 
consulting  the  literature,  the  editor  could  not  help  but  feel  that  when  it 
has  been  properly  digested  and  classified,  a  considerable  advance  will  have 
been  made  toward  raising  the  status  of  the  ductless  glandular  diseases  to  the 
level  of  an  exact  science. 

The  American  and  English  views  mentioned  will  be  found  in  the  adden- 
dum that  is  at  the  end  of  nearly  every  chapter.  If  some  of  these  addenda 
bear  a  too  subjective  tinge  it  is  because  the  editor  in  his  choice  of  the  litera- 
ture was  guided  more  or  less  by  his  personal  experience,  in  which  case  he  may 
not  have  done  full  justice  to  certain  chapters.  Care  has  been  taken,  in  add- 
ing the  new  matter,  not  to  confuse  the  clear-cut  scheme  of  Falta,  who  so 
admirably  separates  the  various  groups  of  ductless  glandular  diseases  by 
well-defined  lines.  This  delimitation  of  the  various  groups  of  ductless  glandu- 
lar diseases  at  the  present  time  is  a  most  desirable  generalization  which  will 
enable  us  to  appreciate  not  only  the  various  parts  which  the  different  duct- 
less glands  play  in  the  make-up  of  an  individual  disease  picture,  but  also 
to  individualize  in  our  diagnosis,  even  as  we  are  now  justified  in  individualiz- 
ing, to  a  certain  extent,  in  the  types  of  Basedow's  disease.  Granted  that  we 
are  not  as  yet  prepared  for  this  along  the  whole  line  of  the  ductless  glandular 
diseases,  it  then  becomes  our  obvious  duty  to  ascertain  what  symptoms  the 
individual  ductless  glandular  diseases,  as  expressed  or  evidenced  in  different 
patients,  have  in  common,  so  that  the  patients  may  be  classed  in  their  re- 
spective groups.  Only  later  will  the  emphasis  of  differences  between  indi- 
viduals of  the  same  group  add  pleasure  and  refinement  to  the  diagnosis,  and 
efficiency  to  the  treatment.  This  is  said  with  a  knowledge  of  the  prevailing 
tendency  of  certain  foreign  schools,  chiefly  the  French,  to  regard  each  indi- 
vidual patient's  condition  as  a  disease  picture  siii  generis;  which  in  truth  in 
one  sense  it  really  is,  but  which,  for  purposes  of  analysis  and  ultimate 
progress,  we  are  not  as  yet  justified  in  regarding  as  such. 


X  EDITOR  S    PREFACE    TO    SECOXD    EDITION' 

As  to  the  text  proper,  but  very  little  difl&culty  has  been  found.  Occa- 
sionally when  the  editor  could  think  of  no  corresponding  English  expression, 
an  approximate  meaning  is  given,  with  the  German  word  in  brackets. 
''Die  Erkrankimgen  der  Blutdrusen"  has  been  translated  "The  Ductless 
Glandular  Diseases,'*  as  forming  a  sufficiently  comprehensive  and  universally 
inteUigible  title.  It  is  especially,  however,  to  the  ductless  glands  with 
more  or  less  well-defined  internal  secretions  (endocrine  organs)  that  our 
author  directs  his  attention,  consequently  such  bodies  as  the  spleen,  the 
diseases  of  which  are  well  described  in  relation  %Wth  those  of  the  hemato- 
poietic system,  and  Luschka/s  gland,  and  the  carotid  body  are  not  here 
considered. 

'■  Ausfallerschienungen'*  has  been  varioush'  translated  "phenomena"  or 
"manifestations""  or  "s3'mptoms"'  due  to  "lack,"'  "deficiency,"  "loss,'" 
"withdrawal,"  "absence"  and  in,  some  cases  "falhng  out."  " tjberlange " 
has  been  translated  "upper  length;"  "Unterlange"  "lower  length."  The 
first  mentioned  of  these  anthropological  measurements  is  taken  from  the 
vertex  to  the  symphysis  pubis,  the  second  from  the  symphysis  to  the  heels 
(according  to  A.  Saenger,  Ueber  Eunuchoidismus,  Deutsche  Zeitschrift  fiir 
Xervenheilkunde.  Bd.  51,  Heft.  5-6,  1914,  p.  192). 

The  author's  hst  of  references  has  been  corrected  to  some  extent,  and  the 
abbre\'iations  of  journals  have  been  changed  to  correspond  to  the  standard 
abbre\aations  of  the  U.  S.  Surgeon  General's  Catalogue.  The  index  has 
been  revised  and  enlarged. 

The  editor's  thanks  are  hereb}*  accorded  to  Messrs.  P.  Blakiston's  Son 

^  Co.  for  the  uniform  kindness  and  courtesy  shown  him  in  the  preparation  of 

this  volume. 

MiLTOX  K.\YTOX  Meyers. 
Pheladelphia. 


EDITORS  PREFACE  TO  SECOND  EDITION 

Advantage  has  been  taken,  on  the  issue  of  a  new  edition,  to  revise 
the  text  thoroughly  and  to  add  a  few  abstracts  of  recent  Hterature  to  the 
addenda. 

MiLTOX  Kaytox  Meyers. 

PHTL-VDELPHIA. 


FOREWORD 

BY 

ARCHIBALD  E.  GARROD,  M.  D.  OXON.,  F.  R.  C.  P.  LOND.,  F.  R.  S. 
PHYSICIAN  TO  ST.  BARTHOLOMEW'S  HOSPITAL,  LONDON 

When  Addison  first  described  the  syndrome  which  has  ever  since  borne 
his  name,  and  proved  its  dependence  upon  destructive  lesions  of  the  adrenal 
glands,  he  broke  ground  in  a  new  field  of  medical  enquiry  of  the  extent  of 
which  neither  he  nor  his  contemporaries  can  have  formed  any  conception. 

The  ductless  glands  had  long  been  known  to  anatomists  as  structures  of 
wholly  obscure  functions,  and  only  in  quite  recent  times  has  any  wide 
knowledge  been  gained  of  the  important  parts  which  they  play  in  the  animal 
economy. 

Indeed  some  thirty  years  elapsed  after  Addison  s  discovery  before  the  next 
step  in  advance  was  achieved  by  the  recognition  of  the  dependence  of  cretin- 
ism and  myxedema  upon  disease  of  the  thyroid  gland.  Since  then  facts 
have  accumulated  rapidly,  yet  hardly  so  rapidly  as  to  keep  pace  with  the 
hypotheses  built  upon  them. 

Nowadays  the  influences  of  the  glands  of  internal  secretion,  in  which 
category  are  included  other  organs  besides  the  glands  which  are  classed  as 
ductless,  hold  a  very  prominent  place  in  medical  thought  and  investigation. 
As  witness  the  many  discussions  which  took  place  in  various  sections  of  the 
17th  International  Medical  Congress,  which  met  in  London  in  1913,  and 
in  many  informal  gatherings  of  its  members  from  all  parts  of  the  civilized 
world. 

Pathological  investigations  have  come  to  the  aid  of  physiological  research 
in  the  elucidation  of  the  functions  of  these  glands  in  health,  and  of  clinical 
medicine  in  the  study  of  the  diseases  to  which  they  are  liable,  and  of  the 
symptoms  by  which  these  diseases  are  revealed.  There  is  indeed  no  de- 
partment of  physiology  in  which  more  has  been  learned  from  the  experiments 
which  Nature  herself  has  carried  out. 

By  the  removal  of  individual  glands,  and  by  observation  of  cases  in  which 
they  have  been  destroyed  by  disease,  we  have  learned  what  results  accrue 
from  withdrawal  of  their  influence,  and  have  even  been  enabled  to  discrimi- 
nate between  the  individual  functions  of  the  parts  of  such  of  these  organs  as 
are  compound  structures.  For  it  is  a  remarkable  example  of  the  economy  of 
Nature  that  in  some  instances  two  or  more  structures  yielding  internal  secre- 


Xll  FOREWORD 

tions  have  been  welded  together  into  a  single  compact  organ.  Thus  the 
chromaffin  medulla  of  the  adrenals  is  clothed  with  the  functionally  distinct 
cortex;  and  the  pituitary  body,  small  as  it  is,  appears  to  be  even  more 
complex. 

That  certain  morbid  states  result  from  loss  of  function  of  particular  glands 
of  internal  secretion  is  a  fact  so  clearly  established  as  to  admit  of  no  two  opin- 
ions. As  regards  the  thyroid  gland,  if  the  effects  of  its  removal  left  any  room 
for  doubt,  the  striking  results  of  the  administration  of  the  gland  substance  in 
cases  of  myxedema  and  cretinism  would  remove  that  doubt.  Nor  is  evi- 
dence lacking  that  such  cases  of  athyroidism  are  but  the  extreme  examples  of 
series  of  cases  of  gradations  of  thyroid  defect  which  bridge  over  the  gap 
which  separates  myxedema  from  normality.  To  describe  such  conditions, 
of  impaired  but  not  abolished  function,  there  have  come  into  use  such  terms 
as  hypothyroidism  and  hypopituitarism. 

Concerning  diseases  of  another  kind,  of  which  exophthalmic  goiter  may 
be  selected  as  the  type,  there  is  no  such  unanimity.  It  is  widely  held  that 
such  conditions  present  the  reverse  of  the  picture,  and  that  they  result  from 
overactivity  of  the  gland  involved,  and  excessive  production  of  its  secretory 
products. 

Many  facts  may  be  adduced  in  support  of  this  theory,  such  as  the  effects 
of  partial  removal  of  the  thyroid  gland  in  exophthalmic  goiter,  and  of  liga- 
ture of  its  arteries,  and  the  results  of  administration  of  thyroid  extract  in 
excess.  Moreover,  there  are  certain  less  obvious  symptoms  which  suggest 
a  converse  to  myxedema.  For  example  the  exalted  tolerance  of  carbohy- 
drates, which  is  a  feature  of  myxedema,  as  contrasted  with  the  so  frequent 
lowering  of  tolerance  in  exophthalmic  goiter.  Such  evidence  is  fully  set 
forth  by  Professor  Falla  in  this  work,  for  he  is  a  staunch  upholder  of  the  view 
that  all  the  morbid  symptoms  which  result  from  diseases  of  the  glands  of 
internal  secretion,  so  far  as  they  can  be  ascribed  to  their  secretory  functions, 
are  attributable  either  to  depression  or  exaltation  of  the  function  of  the  gland 
concerned. 

However,  there  are  some,  who  are  entitled  to  speak  with  authority,  who 
are  unable  to  accept  this  interpretation,  and  who  hold  that  the  maladies  so 
often  ascribed  to  excessive  functional  activity  are  rather  due  to  perversion 
of  function,  and  the  production  by  the  gland  concerned  of  an  abnormal  secre- 
tion. Such  terms  as  dysthyroidism  and  dyspituitarism  are  used  to  express 
this  conception. 

The  arguments  adduced  in  its  favor  are  of  several  kinds.  It  must  be 
acknowledged  that  the  administration  in  excess  of  the  active  principle  of  the 
thyroid  gland,  although  it  brings  about  exaltation  of  the  metabolic  processes 
in  strict  contrast  to  the  depression  of  those  processes  observed  in  myxedema, 
and  produces  some  of  the  symptoms  of  exophthalmic  goiter,  does  not  repro- 
duce the  picture  of  that  disease  so  exactly  as  to  place  its  origin  in  excessive 


FOREWORD  XIU 

functional  activity  of  the  gland  beyond  all  question.  Again  it  is  urged  that 
it  is  difficult  to  conceive  of  overfunction  as  resulting  from  disease,  which 
might  rather  be  expected  to  impair  the  acti\-ities  to  a  greater  or  less  extent. 

As  against  this  it  may  be  urged  that  it  is  equally  hard  to  imagine  a  per- 
version of  the  metabolic  changes  into  new  hnes.  other  than  those  in  which  the 
several  protein  fractions,  and  even  the  several  carbohydrates,  are  normally 
dealt  with,  stage  by  stage,  by  specialized  enzymes. 

The  more  the  internal  secretions  are  studied  the  more  clearly  it  is  being 
reahzed  how  wide  is  the  field  of  their  activities.  We  are  learning  that,  in 
addition  to  the  control  of  metaboHsm,  or  rather  in  virtue  of  that  control,  the 
endocrine  glands  exert  immense  influence  upon  growth  and  development; 
and  their  their  hormonic  functions  are  exercised  now  in  the  direction  of  stimu- 
lation, and  now  in  that  of  restraint.  Indeed  it  is  not  possible  to  conceive 
of  a  control  which  is  wholly  one-sided;  the  controlling  agent  must  be  able  to 
curb  as  well  as  to  urge  on.  So  we  are  led  to  think  of  inhibiting  as  well  as 
exciting  hormones,  if  that  term  may  be  so  perverted  from  its  hteral  meaning. 

In  addition  to  our  more  exact  knowledge,  so  encouraging  in  its  progress, 
although  as  yet  so  incomplete,  of  the  work  of  the  indi\ddual  glands,  we  begin 
to  see  e\-idences  of  an  interaction  of  the  organs  of  internal  secretion,  as  mem- 
bers of  a  group  of  immense  influence,  a  hormonpoietic  system.  Here  we  are 
stepping  on  to  far  less  firm  ground  than  we  have  hitherto  trodden,  and  we 
need  to  move  with  caution  lest  our  hypotheses  carry  us  further  than  our  facts 
warrant.  Yet  the  evidence  is  at  the  least  highly  suggestive.  We  see  how 
removal  of  a  single  gland,  by  operation  or  disease,  is  followed  by  changes  in 
other  glands  of  the  group — changes  which  are  best  explained  by  removal 
of  a  wonted  stimulus  or  withdrawal  of  a  regulating  control. 

^Moreover  there  is  e\-idence,  as  Claude  and  Gougerot  were  the  first  to 
point  out,  that  the  various  glands  of  internal  secretion  may  be  attacked  simul- 
taneously by  a  morbid  process  which  is  described  as  pluriglandular  sclerosis. 
Where  this  is  the  case  the  cHnical  picture  presents  elements  of  the  several 
syndromes  which  result  from  depression  of  function  of  the  indi^ddual  glands 
of  the  group.  Thus  there  are  suggestions  of  h}'perthyroidism,  of  pituitary 
defect,  of  genital  h\-poplasia,  and  of  Addison's  disease,  side  by  side  in  the 
same  patient. 

The  interrelation  of  the  endocrine  glands  and  the  nervous  system  is  yet 
another  subject  full  of  interest,  and  which  receives  full  consideration  in  Pro- 
fessor Falta's  pages.  How  close  is  the  control  exerted  by  the  vegetative 
nervous  system  over  the  organs  of  internal  secretion  is  brought  home  to  us 
when  we  consider  such  phenomena  as  puncture  glycosuria.  It  may  now  be 
taken  as  proven  that  the  impulse  conveyed  to  the  adrenals  by  the  splanchnic 
nerves  excites  a  temporary  excess  of  secretion  of  these  glands,  and  to  this  the 
excretion  of  sugar  is  due.  Thus  it  is  suggested  that  not  a  few  phenomena, 
attributable  to  nervous  impulses,  are  produced  through  the  instrumentahty 


XIV  FOREWORD 

of  the  endocrine  glands,  and  the  symptoms  referable  to  disturbances  of  their 
functions  are  not  necessarily  due  to  actual  disease  of  these  organs.  It  may  be 
that  such  is  the  explanation  of  much  which  is  still  obscure  as  to  the  part 
played  by  the  pancreas  in  diabetes. 

The  literature  of  internal  secretions  is  already  a  very  large  one,  and  in 
the  monumental  work  of  Biedl  we  have  set  before  us  all  that  is  known  of  the 
subject  from  the  standpoints  of  physiology  and  experimental  pathology. 

The  present  work  has  a  different  scope  and  aim.  In  it  the  maladies  of 
the  hormonopoietic  system  are  for  the  iirst  time  discussed  in  a  single  volume, 
and  from  the  clinical  standpoint.  It  will  be  welcomed  by  members  of  the 
medical  profession  in  all  lands,  for  in  it  will  be  found  accurate  and  detailed 
descriptions  of  the  symptom  groups  which  have  their  origin  in  lesions  of  the 
glands  of  internal  secretion,  and  also  of  some  diseases  for  which  such  an  origin 
has  been  suggested. 

It  is  all  the  more  valuable  because  it  is  the  work  of  a  physician  who  com- 
bines bedside  observation  with  experimental  research  in  the  laboratory. 
Professor  Falta's  important  contributions  to  our  knowledge  of  pathological 
chemistry  are  widely  known,  and  he  has  been  led  on  to  the  study  of  the  regu- 
lators of  metabolism  by  his  interest  in  the  chemical  processes  which  it  is 
their  function  to  control. 


CONTENTS 

CHAPTER  I 

Page 

General  Part :    .    .    .    .  1-52 

Historical  Development  and  Definition i 

Reciprocal  Action  of  the  Ductless  Glands 3 

Question  of  Dysfunction 10 

Influence  of  the  Ductless  Glands  on  the  Growth I3- 

Influence  of  the  Ductless  Glands  on  the  Regulation  of  Metabolism "    .    .  16 

Embryology  of  the  Ductless  Glandular  System 20 

Grouping  of  the  Ductless  Glands 22 

Relationship  between  the  Ductless  Glandular  System  and  the  Nervous  System     .  23 

A.  Influence  of  the  Ductless  Glandular  System  on  the  Nervous  System  ...  24 

B.  Influence  of  the  Nervous  System  on  the  Function  of  the  Ductless  Glandu- 

lar System 32 

Influence  of  the  Ductless  Glands  on  the  Hematopoietic  Apparatus 33 

Pathogenesis  and  Etiology  of  the  Ductless  Glandular  Diseases 35 

Relation  between  Diseases  of  the  Central  Nervous  System  and  the  Ductless  Glandu- 
lar System 37 

Pluriglandular  Disturbances 42 

The  Ductless  Glands  and  Constitution ' 45 

Addendum 49 

CHAPTER  II 

The  Diseases  of  the  Thyroid  Gland 53-153 

Anatomy  and  Embryology 53 

Tumors  of  the  Thyroid  Gland 54 

Inflammations  of  the  Thyroid  Gland 55 

(c)    Morbus  Basedowi — Hyperthyrosis 57- 

Historical  and  Definition 57 

Occurrence  and  Symptomatology 57 

Pathogenesis 84 

Etiology 93 

Forms  of  Basedow's  Disease 94 

Diagnosis 98  * 

Prognosis  and  Treatment • 98 

(&)    Athyrosis  or  Hypothyrosis 103 

Historical      103 

1,  Myxoedema  Adultorum  or  Cachexia  Thyreopriva  Adultorum 104* 

Definition 104 

Occurrence  and  Symptomatology    .    .    .    .    - 104 

Etiology  and  Course ii7 

Differential  Diagnosis 118 

2.  Sporadic  Cretinism 120- 

Definition 120 

Symptomatology 123 

Differential  Diagnosis 138 

Treatment  of  Athyrosis  or  Hypothyrosis 139 

Addendum I44 

XV 


XVI  CONTENTS 

CHAPTER  III 

Page 

The  Cretinic  Degeneration 154-173  • 

1.  Goiter 155 

2.  Goiter-heart 156 

3.  Endemic  Cretinism 158 

Symptomatology   .  * 158 

Endemic  Mutism 161 

Treatment - 165 

Pathogenesis 169 

Differential  Diagnosis 171 

Addendum 172 

CHAPTER  IV 

Diseases  of  the  Parathyroid  Glands 174-222 

Anatomy 174 

Embryology 175 

Historical      176 

(a)    Aparathyrosis  or  Hypoparathyrosis,  Tetany 177 

Definition 177 

Symptomatology 177 

Pathogenesis  of  Tetany      200 

Forms  of  Tetany  and  Pathological  Anatomy 207 

1.  The  Parathyroprivic  or  Traumatic  Tetany 207 

2.  Tetany  in  Diseases  of  the  Thyroid  Gland 209 

3.  Tetany  in  Infectious  Diseases  and  Intoxications 209 

4.  Idiopathic  Tetany  (Occupation  Tetany) 210 

5.  The  Tetany  of  Children 212 

6.  The  Tetany  of  Maternity 213 

7.  Tetany  in  Gastrointestinal  Diseases 214 

Differential  Diagnosis 216 

Prognosis  and  Treatment 218 

{b)     Condition  of  Hyperfunction  of  the  Parathyroid  Glands 220 

Addendum 221 

CHAPTER  V 

Diseases  of  the  Thymus  Gland 223-230 

Anatom}-  and  Embryology 223 

Physiology .    .  223 

Pathology  and  Semiology 225 

Addendum 229 

CHAPTER  VI 

Diseases  of  the  Hypophysis 231-328 

Anatomy  and  Embryology 231 

(a)  Acromegaly 235 

Definition 235 

Occurrence  and  Symptomatology 235 

Pathological  Anatomy 267 

Pathogenesis 269 

Early  Acromegaly 277 

Differential  Diagnosis 280 

Treatment 281 

(b)  Hypophysial  Dystrophy 282 

Historical      282 


CONTENTS  XVll 

Page 

Definition 283 

Symptomatology 283 

The  Metabolism 280 

Pathogenesis 3I5 

Differential  Diagnosis 324 

Treatment 325 

Therapeutic  Use  of  the  Hypophysis  Extracts 326 

Addendum 327 

CHAPTER  VII 

Diseases  of  the  Epiphysis      329~333 

Anatomy  and  Embryology 329 

Pathological  Anatomy  and  Symptomatology 330 

Diagnosis  and  Treatment 332 

Addendum 333 

CHAPTER  VIII 

Diseases  of  the  Suprarenal  Apparatus 334-364 

Anatomy  and  Embryology 334 

(a)    Condition  of  Hypofunction  of  the  Suprarenal  Apparatus 336^ 

1.  Addison's  Disease 336 

Definition 336 

Symptomatology 336 

Course 338 

Pathological  Anatomy 338 

Pathological  Physiology  of  the  Suprarenals 342 

Pathogenesis  of  Addison's  Disease 346 

Differential  Diagnosis 347 

Prognosis  and  Treatment      348 

2.  Isolated  Phenomena  due  to  Failure  of  Function  of  the  Suprarenal  Corte.K      .    .351 
{b)    Conditions  of  Hyperfunction  of  the  Suprarenal  Apparatus 352  ♦ 

1.  Tumors  that  Proceed  from  Chromaffin  Tissue      352 

2.  Tumors  that  Proceed  from  the  Cortex 356 

Treatment 363 

3.  Tumors  of  the  Suprarenal  Gland  that  Apparently  Consist  in  Cortex  and  Medulla.  363 
Addendum 363 

CHAPTER  IX  - 

Status  Lymphaticus  and  Status  Hypoplasticus 365-368 

A.  Status  Lymphaticus 365 

B.  Status  Hypoplasticus 367 

CHAPTER  X 

Diseases  of  the  Sexual  Glands 369-439 

Embryology,  Anatomical  and  Physiological  Preliminary  Remarks 370 

A.  The  Interstitial  Glands 370 

B.  The  Generative  Apparatus 374 

Pregnancy 377 

I.   The  Malformations 385 

1.  Aplasia  of  the  Sexual  Glands 385 

2.  Hermaphroditism 386 

II.  Agenitalism,  or  Hypogenitalism " 391 

I.  Eunuchs 391 

Occurrence  and  Symptomatology 391 


XVlll  CONTEXTS 

Page 

2.  Late  Castrates 394 

3.  Eunuchoidism 397 

Definition 397 

Historical  and  Case  Histories       397 

Symptomatology 405 

Occurrence  and  Pathogenesis 410 

Differential  Diagnosis 410 

Prognosis  and  Treatment      412 

4.  Late  Eunuchoidism 413 

Historical 413 

Definition 414 

Case  Reports       414 

Symptomatology 418 

Differential  Diagnosis    .    .    : 421 

Treatment 422 

5.  Treatment  of  Genital  Glandular  Insufficiency 422 

in.  Hypergenitalism 424 

Definition      424 

Pathologico-anatomical  Findings      424 

Symptomatology 424 

Treatment 427 

IV.   Chlorosis 426 

Historical 426 

Symptomatology 428 

Pathogenesis 431 

Appendix,  Osteomalacia 435 

Addendum 438 

CHAPTER  XI 

Pluriglandular  Diseases 440-463 

Multiple  Ductless  Glandular  Sclerosis 440 

Historical      441 

Definition 442 

Case  Reports 442 

Symptomatology 445 

Differential  Diagnosis 453  . 

Treatment 453 

Gigantism      454 

Historical 454 

Symptomatology 455 

Pathogenesis 461 

CHAPTER  XII 

Vegetative  Disturbances  that  do  not  depend  Directly  on  Diseases  of  the  Ductless 

Glands  464-498 

I.   Infantilism 465 

Historical 465  ■^ 

Definition 468 

Symptomatology 472 

Forms  and  Etiology      474 

Differential  Diagnosis 475 

Pathogenesis 479 

Prognosis  and  Treatment 479 

II.    Trtie  Dwarfism 480'' 


COXTEXTS  XIX 

Page 

Historical 480 

Primordial  Nanosonaia      480 

Paltauf' s  Dwarf 481 

III.  The  Rachitic  Dwarf 384 

IV.  Chondrodystrophy 484 

Historical 484 

Definition 485 

Symptomatology- 485 

Occurrence      491 

Etiology- 493 

Differential  Diagnosis 493 

V.   Mongolism 494 

S3'mptomatolog\- 494 

Pathogenesis  and  Treatment 497 

Addendum 497 

CHAPTER  Xni 

Diseases  of  the  Insular  Apparatus  of  the  Pancreas  and  Their  Relation  to  Diabetes 

MeUitus 499-569 

Historical  Development 499 

Anatom\-  and  Embr3-olog\- 501 

I.  Experimental  Part 503 

A.  Diabetes  after  Extirpation  of  the  Pancreas 503 

B.  Experimental  Ker\-ous  Diabetes 515 

II.   Clinical  Part 518 

A.  Gross  Anatomical  Disturbances 518 

B.  Genuine  Diabetes  MeUitus 526 

The  Carbohydrate  ]Metabolism 527 

The  Protein  JMetabolism 529 

The  Water  Equilibrium 530 

The  Respiratory-  ^letaboUsm 531 

Vegetative  Ner^^ous  System 540 

Pathological  Anatomy  of  Diabetes  AleUitus        546 

Theoretical '. 561 

Differential  Diagnosis 566 

Addendum 568 

CHAPTER  XIV 

The  Different  Formi.  A  Obesity  and  Adipositas  Dolorosa       570 

A.  The  Different  Forms  of  Obesity 570 

1.  Pancreatogenic  Obesity 572 

2.  Thyrogenic  Obesity 573 

3.  Dystrophia  Adiposo-genitaHs 574 

4.  Epiphysial  Obesity       575 

B.  Adipositas  Dolorosa 575 

Historical 575 

Symptomatology 581 

Pathological  Anatomy      583 

Pathogenesis       584 

Differential  Diagnosis 587 

Treatment 587 

Addendum      587 

Literature 590 

Index 659 


THE  DUCTLESS  GLANDULAR  DISEASES 

CHAPTER  I 

GENERAL  PART 

Historical  Development  and  Definition 

The  clinical  delimitation  of  a  group  of  the  disease  pictures  which  to-day 
are  known  as  diseases  of  the  ductless  glands  is  to  a  certain  extent  very  much 
older  than  the  conception  of  the  idea  of  internal  secretion  as  elaborated  by 
experimental  pathology.  The  profound  alterations  in  the  bevelopment  of 
the  human  organism  after  removal  of  the  sexual  glands  in  early  life  are  too 
remarkable  not  to  have  awakened  the  interest  of  physicians  and  the  laity 
as  early  as  the  days  of  antiquity.  The  breeders  of  animals  had  made  use  of 
empirical  knowledge  long  before  the  question  was  discussed  as  to  in  which 
way  the  sexual  glands  influence  the  formation  of  the  body  and  its  dis- 
tribution of  fat.  A  material  progress,  however,  in  the  development  of 
the  clinical  aspects  of  the  diseases  of  the  ductless  glands  began  only  about 
the  middle  of  the  19th  century.  It  is  associated  indissolubly  with  the  name 
of  Thomas  Addison.  Addison  in  1855,  on  the  ground  of  pathologico-anat- 
omical  findings,  referred  the  sickness  that  bears  his  name  to  a  destruction 
of  both  suprarenal  glands.  Then  after  Gull,  Ord,  and  Charcot  had  described 
myxedema  clinically,  Theodore  Kocher  and  Reverdin,  in  1882  and  1883, 
demonstrated  that  this  disease  picture  is  due  to  the  absence  of  the  functional 
activities  of  the  thyroid  gland.  We  must  regard  the  year  1886  as  a  further 
landmark  in  the  history  of  the  diseases  of  the  ductless  glands.  In  this 
year  Mdbius  first  expressed  the  idea  that  a  disease  picture — Basedow's 
disease — depends  on  an  abnormally  increased  activity  of  a  ductless  gland. 
First  in  the  year  1889  Brown-Sequard  reported  to  the  Biological  Society  of 
Paris  concerning  experiments  that  made  it  seem  as  though  the  ductless 
glands  furnished  to  the  blood  substances  that,  when  carried  by  the  blood 
to  distant-lying  organs,  influenced  these  extensively.  Brown-Sequard  in- 
jected juice  of  the  testicle  subcutaneously  into  his  own  body  and  observed 
an  increase  in  corporeal  and  mental  powers  that  he  attributed  to  the  in- 
fluence of  these  injections.  It  is  true  that  Johannes  Aluller,  Ruysch,  and 
other  authors  preceded  Brown-Sequard;  it  was,  however,  Brown-Sequard  who 
first  clearly  formulated  these  thoughts,  based  them  on  experiments,  and 
thus  attracted  the  general  interest  of  the  medical  world  to  them.  With 
the  extension  of  experimental  pathology,  disease  pictures  that  had  formerly 
been  regarded  as  nervous  diseases  or  constitutional  diseases  were  added  to 


2  GENERAL   PART 

the  new  disease  group  in  rapid  succession.  The  discovery  of  pancreatic 
diabetes  by  von  Mering  and  Minkoivski  placed  the  pancreas  as  the  central 
figure  in  the  pathogenesis  of  diabetes  mellitus.  Then  later  came  the  studies 
of  Schulze  and  Ssoholew  as  to  the  physiological  and  pathological  independence 
of  the  insular  apparatus,  and  of  Opie,  SaUykow,  Weichselhaum  and  others  as 
to  the  histological  alterations  in  the  insular  apparatus  in  diabetes  mellitus. 
The  very  much  later  discovery  by  Blum  of  the  glycosuric  action  of  the 
suprarenal  extract  and  the  knowledge  that  "sugar  puncture"  produces 
discharge  [of  the  secretion]  of  the  suprarenal  through  conduction  to  the 
chromaffin  tissue  by  way  of  the  sympathetic  paths  have  again  brought  about 
partial  recognition  of  neurogenic  origin  of  diabetes  as  first  advocated  by 
Claude  Bernard.  For  clinical  purposes  the  chromaffin  tissues  won  recog- 
nition through  the  teaching  of  Wiesel,  that  hypertonia  in  contracted  kidney 
originates  through  hyperplasia  of  the  chromaffin  tissue,  and  through  the 
recognition  that  in  status  lymphaticus  the  chromaffin  tissue  is  ordinarily 
found  to  be  hypoplastic  {Wiesel,  Hedingcr).  "Thyroid  tetany"  was  dis- 
covered experimentally  by  Schiff  and  clinically  by  A".  Wein.  The  discovery 
of  parathyroprivic  tetany  by  G/gy,  Vassale,  a.nd  Generali  dissociated,  however, 
the  symptoms  of  tetany  from  those  of  absence  of  the  thyroid  gland  and 
ascribed  to  the  parathyroid  gland  the  decisive  role  in  pathogenesis  of  the 
individual  forms  of  tetany  {Jeandelize,  Pineles,  Erdheim,  CJivosiek).  After 
Pierre  Marie  had  already  brought  the  disease  acromegaly,  which  had  been 
described  by  him,  into  relation  with  the  hypophysis,  the  fact  became  gen- 
erally recognized  that  not,  as  was  originally  thought,  a  diminution  but  an 
increase  in  function  of  the  hypophysis  brought  about  this  disease;  while  in 
1901  A.  Frohlich  and  after  him  especially  v.  Frankl-Hochwart  distinguished  a 
disease  type,  in  many  respects  the  anti-type  of  acromegaly,  that  through 
the  newer  investigations  of  experimental  pathology  can  be  regarded  as  the 
sequel  of  a  diminution  of  function  of  this  organ.  The  pathological  anatomy 
of  the  hypophysis  was  especially  advanced  by  Benda,  who  established  the 
adenomatous  character  of  the  hyperplasia  of  the  hypophysis  in  acromegaly, 
and  by  the  studies  of  ErdJieim  on  squamous  epithelioma  in  hypophysial 
dystrophy.  The  histology  of  the  struma  of  Basedow's  disease  was  thor- 
oughly studied  earher.  The  pathogenetic  place  of  the  thyroid  then  won 
further  significance  through  the  operative  treatment  of  Basedow's  disease 
{Rehn,  Kocher,  and  others),  and  through  the  study  of  its  relationship  to 
sporadic  cretinism  ("thyreoaplasie"  of  Pineles),  to  endemic  cretinism 
{V.  Wagner,  H.  6°  E.  Birchcr,  Ewald,  Scholz)  and  to  goiter  heart  {Fr.  Kraus). 
Also  the  significance  of  the  sexual  glands  for  many  disease  pictures  was 
more  exactly  studied.  Eunuchoidism  was  sharply  dehneated  by  Tandler 
and  Grosz,  and  the  clinical  symptomatology  of  pmareture  development  of 
the  sexual  glands  was  more  widely  developed.  Then  were  added  new 
investigations  as  to  the  relation  of  the  epiphysis  [pineal  gland]  (}[arhurg, 


HISTORICAL    DEVELOPMENT    AND    DEFINITION  3 

V.  Frankl-H ochwart)  and  the  suprarenal  cortex  to  premature  development. 
Only  the  thymus  gland  has  not  as  yet  found  a  secure  position  in  the  sympto- 
matology of  the  disease  of  the  ductless  glands.  Finally,  the  symptomatol- 
ogy of  multiple  ductless  glandular  sclerosis  has  been  more  sharply  delimited 
under  the  multiform  syndrome  of  "insuffisance  pluriglandulaire"  described 
by  Claude  and  Gougerot,  and  from  it  has  been  separated  the  disease  picture 
of  isolated  late  eunuchoidism. 

These  few  examples  may  suffice  to  furnish  an  idea  of  the  impetus  that  the 
clinical  aspects  of  the  disease  of  the  ductless  glands  have  assumed  in  the  last 
decade.  The  advance  in  experimental  pathology  and  especially  in  physio- 
logical chemistry  has  really  not  kept  pace  with  this  development  of  clinical 
pathology  and  the  extension  of  pathological  anatomy.  I  do  not  mean  to 
belittle  the  significance  of  what  has  been  brought  to  recognition  through 
experimental  pathology;  this  alone  has  made  possible  the  rapid  advance  of 
the  clinical  side;  I  only  wish  to  say  that  the  deficient  knowledge  of  the 
chemical  nature  of  the  active  substances  given  ofl"  by  the  ductless  glands 
constitutes  the  weak  point  in  the  knowledge  of  the  internal  secretions  and 
explains  why  even  to-day  we  are  very  often  compelled  to  work  with  hazy 
ideas.  But  even  in  this  direction  significant  accretions  [to  our  knowledge] 
are  present;  we  can  say  that  through  the  isolation  and  chemical  definition 
of  adrenalin  {Takamine)  and  through  the  knowledge  that  this  body  of  re- 
latively simple  chemical  structure  and  eminent  physiological  activity  is  the 
specific  secretion  of  the  chromaffin  system,  the  foundation  stone  has  been 
laid  for  the  physiological  chemistry  of  the  internal  secretions.  Experi- 
mental pathology  entered  here  most  opportunely,  and  acted  prominently 
in  the  discovery  of  the  manifold  actions  of  this  substance  and  its  points  of 
attack  on  the  organs  afi'ected  by  the  sympathetic  nerves.  The  isolation 
of  adrenalin,  it  is  known,  followed  from  that  of  iodthyroglobulin  (Baumaiiu, 
Oswald).  In  this  case,  however,  sHght  doubts  are  still  present  as  to  whether 
we  have  in  iodthyroglobulin  the  specific  internal  secretion  of  the  thyroid 
in  purest  form.  Then,  too,  we  are  very  much  less  exactly  informed  as  to 
its  way  of  action  and  points  of  attack.  The  knowledge  of  the  specific 
secretion  of  the  other  ductless  glands  is  as  yet  extremely  faulty.  Of  the 
suprarenal  cortex  we  only  know  that  it  contains  cholin,  a  body  of  con- 
siderable physiologic  activity  that  is  distributed  otherwise  in  the  organism. 
That,  however,  we  have  in  choHn  a  specific  secretion  of  the  suprarenal  cortex 
is  improbable.  It  has  been  possible  recently  to  obtain  from  the  lobes  of 
the  hypophysis  extracts  of  great  physiologic  importance  that  have  alreadv 
secured  for  themselves  a  place  in  therapeutics;  but  there  are  wanting  the 
chemical  definition  and  the  demonstration  that  these  bodies  are  given  oft" 
to  the  blood.  All  postulates  that  we  must  ascribe  to  a  substance  in  order 
that  we  may  regard  it  as  the  specific  secretion  of  the  ductless  gland  in  question 
have  not  as  yet  been  fulfilled  by  any  of  the  hormones.     We  must  ascertain: 


4  GENERAL    PART 

1.  That  the  substance  in  question  be  found  in  the  efferent  blood-path  or 
lymph-path. 

2.  That  after  experimental  extirpation  of  the  ductless  gland  in  question 
the  symptoms  due  to  the  removal  are  combated  by  peroral  or  sub- 
cutaneous administration. 

3.  That  through  the  long-continued  administration  of  this  substance 
manifestations  are  ehcited  that  are  similar  to  those  which  cHnical 
evidence  leads  us  to  regard  as  the  symptoms  following  upon  increased 
function,  a  conception  that,  as  the  results  of  the  surgical  therapy  of 
these  conditions,  has  in  recent  years  been  made  certain. 

All  these  postulates  are  not  fulfilled  in  the  case  of  adrenalin.  Adrenalin 
has  been  demonstrated  in  the  blood  of  the  suprarenal  vein,  but  the  relation- 
ship to  clinical  medicine  is  still  lacking  in  clearness.  In  the  case  of  iodthy- 
roglobulin,  the  demonstration  in  the  blood  or  the  lymph  is  as  yet  lacking. 
Hypophysis  extract  has  as  yet  not  been  studied  enough,  so  that  we  can- 
not say  that  it  fulfills  any  of  these  postulates.  As  far  as  the  other  ductless 
glands  are  concerned  (for  example,  the  insular  apparatus  of  the  pancreas,  or 
the  parathyroid  glands),  the  significance  of  which  in  experimental  or  clinical 
pathology  is  extraordinarily  imperfect,  we  have  not  as  yet  succeeded  in 
obtaining  active  extracts,  or  we  are  not  at  all  certain  that  the  observed 
actions  of  the  extracts  are  specific.  The  physiological  chemistry  of  the 
internal  secretions  is  still  in  its  childhood.  From  it  alone,  however,  is  a 
sharp  definition  of  the  disease  picture  to  be  expected;  the  chemical  demon- 
stration of  the  specific  substances  in  the  blood  even  in  combined  form,  the 
possibility  of  the  demonstration  that  these  substances  in  lessened,  normal,  or 
increased  quantities  circulate  in  the  blood,  would  be  of  great  importance  for 
clinical  medicine.  The  biological  method  in  this  direction  has  up  to  the  pres- 
ent failed.  The  chemical  definition  and  isolation  in  pure  form  of  these  spe- 
cific substances  will  also  furnish  an  important  advance  in  the  therapy  of  the 
diseases  due  to  lack  of  these  glandular  substances  in  the  organism.  The 
domain  of  the  internal  secretions  constitutes  for  physiological  chemistry  an 
inexhaustible  field  for  labor  that  theoretically  and  practically  represents  a 
rich  reward. 

The  backwardness  of  the  physiologico-chemical  knowledge  in  this 
territory  explains  why  it  has  not  been  possible  up  to  the  present  to  obtain  a 
clear  definition  of  the  idea  of  internal  secretion.  According  to  the  original 
assumption,  we  understand  by  internal  secretion  the  giving  oft'  of  physio- 
logically active  substances  into  the  circulation,  of  substances  that  through 
their  action  on  distantly-lying  organs  act  in  a  regulatory  manner  on  the 
complex  processes  sustaining  life.  According  to  this  general  definition,  how- 
ever, every  tissue  in  the  animal  body  really  yields  an  internal  secretion,  as 
von  Krehl  has  already  pointed  out.  The  point  of  emphasis  in  this  defini- 
tion lies  in  the  assumption  of  a  chemical  correlation  of  the  individual  organs 


HISTORICAL    DEVELOPMENT    AND    DEFINITION  5 

of  the  body  in  contradistinction  to  the  assumption  of  a  nervous  correlation, 
which  formerly  was  almost  all-sufficient.  This  distinction  is  indeed  not  to  be 
maintained  so  rigidly  for,  as  we  shall  see  later  on,  it  must  be  assumed  that 
to  many  specific  ductless  glandular  secretions  must  be  ascribed  an  important 
and,  after  its  fashion,  a  quite  definite  influence  on  the  condition  of  excita- 
tion of  the  nervous  system.  We  cannot  indeed  exclude  the  question  as  to 
whether  the  action  of  the  ductless  glandular  secretions  does  not  come  about 
through  alterations  in  the  metabolic  processes  in  the  various  parts  of  the 
somatic  and  vegetative  neurones  (ganglion-cells,  myoneural  junctions,  etc.). 
A.  Biedl  happily  expresses  these  changes  in  our  views  by  the  dictum:  "For- 
merly every  correlation  of  organs  was  regarded  as  nervous;  to-day,  however, 
even  nervous  actions  are  regarded  as  brought  about  chemically."  Bayliss 
and  Starling  have  found  that  under  the  influence  of  the  acid  gastric  juice 
upon  the  epithehal  cells  of  the  intestinal  mucosa  a  substance  is  secreted  by 
the  latter  that  brings  about  through  the  circulation  the  secretion  of  pan- 
creatic juice.  They  call  such  chemical  messengers  hormones  (from  o^^aw  = 
I  call),  a  designation  that  now  has  found  almost  general  use  also  as  applied 
to  the  specific  secretions  of  the  ductless  glands.  With  such  a  general 
application  of  the  meaning  of  the  internal  secretions,  not  much  is  to  be 
gained  for  clinical  purposes,  as  may  readily  be  seen.  Nor  is  a  morphological 
definition  of  the  ductless  glands  possible,  as  Biedl  has  pointed  out.  The  histo- 
logical structure  of  the  individual  ductless  glands  varies  according  to  their 
genesis  from  the  dift'erent  germinal  layers.  Whether  the  specific  secretions 
of  the  ductless  glands  are  to  be  separated  from  the  other  hormones  through 
their  chemical  characteristics  cannot  be  answered  at  all  at  the  present  day. 
Anatomy,  morphology,  embryology,  experimental  physiology,  and  patholog- 
ical chemistry  do  not  furnish  to-day  a  satisfactory  characterization  of  the 
ductless  glandular  system.  Up  to  the  present,  the  demonstration  that  an 
individual  ductless  gland  belongs  to  a  system  is  furnished  most  distinctly 
by  clinical  observation,  particularly  by  the  intimate  reciprocal  relations  of 
the  ductless  glands  under  physiological  and  pathological  conditions. 

It  appears  to  me,  therefore,  that  first  and  foremost  it  is  more  important  for 
the  clinical  point  of  view  not  to  associate  the  meaning  of  internal  secretion 
exclusively  with  the  ductless  glands.  I  might  formulate  this  standpoint  in 
the  following  way:  probably  very  many  cell-complexes  of  the  animal  organ- 
ism possess  an  internal  secretion.  We  may  designate  the  totality  of  all  cell- 
complexes  provided  with  an  internal  secretion  a  hormonopoietic  system.  There 
are,  however,  a  series  oj  organs  the  proper  function  of  which  we  7nnst  regard  as  the 
production  of  especially  important  hormones,  which  are  provided  with  powerful 
physiological  characteristics.  It  is  a  common  property  of  these  organs  that  they 
separate  out  their  specific  secretion  directly  into  the  blood-path.  We  therefore 
call  them  ductless  glands,  and  their  collective  total  the  ductless  glandular  system. 

The  recognition  that  the  ductless  glands  form  a  system  was  of  great  sig- 


6  GENERAL   PART 

nificance  for  the  clinical  aspects  of  the  diseases  of  the  ductless  glands.  This 
recognition,  that  was  especially  furnished  by  the  serviceable  work  of  Plneles, 
depends  not  only  upon  the  observations  of  intimate  physiological  reciprocal 
relations,  but  also  upon  numerous  clinical  experiences  and  pathological- 
anatomical  findings  that  show  that  diseases  very  frequently  affect  several 
ductless  glands  simultaneously,  and  lead  not  only  to  simultaneous  increase  of 
function,  but  also  to  simultaneous  diminution  in  function,  or  to  a  combination 
of  increase  of  function  in  some  of  these  organs  and  to  diminution  of  func- 
tion in  others. 

Reciprocal  Action  of  the  Ductless  Glands 

I  would  like  here  to  enter  a  little  more  fully  into  the  question  of  the  re- 
ciprocal action  of  the  ductless  glands;  the  phrase  has  become,  as  Novak  says, 
a  catchword.  An  immense  amount  of  work  in  recent  years  has  been  de- 
voted to  the  study  of  this  reciprocal  action,  and  hypotheses  and  speculations 
have  grown  luxuriantly  upon  this  soil.  It  is  true  that  up  to  the  present 
we  really  know  nothing  exactly  concerning  the  intimate  process  in  these 
reciprocal  actions,  but  in  a  clinical  relation  such  correlations  force  themselves 
unmistakably  upon  the  observer;  the  knowledge  of  them  makes  easier  the 
analysis  of  the  often  complicated  disease  picture.  Finally,  the  expressions 
"reciprocal  reinforcement"  or  "reciprocal  inhibition"  are  in  the  first  place 
nothing  other  than  circumlocutions  for  [clinical]  observations.  If  we  view 
the  thing  from  this  standpoint  it  seems  to  me  that  the  study  of  these  corre- 
lations is  productive. 

For  the  understanding  of  these  often  very  complicated  processes  it  seems 
to  me  that  a  separation  of  physiological  and  pathological  correlations  becomes 
absolutely  necessary.  Among  pJiysiological  correlations  I  mean  to  include 
the  action  that  the  alteration  of  function  of  a  ductless  gland — diminution 
or  increase  of  function — exercises  u]:)on  the  function  of  another  otherwise 
normal  ductless  gland.  These  conditions  are  fulfilled  in  an  ideal  manner, 
when  the  ductless  gland  has  been  extirpated,  for  example.  This  can  occur  in 
human  pathology.  I  have  reference  to  the  total  extirpation  of  the  thyroid 
gland  which,  formerly,  before  we  knew  about  the  incurable  results  of  the 
operation,  was  also  undertaken  in  human  beings;  or  to  parathyroprivic 
tetany  after  operations  on  the  thyroid  gland;  or  to  castration.  Further, 
an  inflammatory  process  may  become  established  in  an  isolated  ductless 
gland  and  cause  its  destruction.  In  such  cases  we  must  by  all  means  be 
very  careful  as  to  the  assumption  of  a  pure  physiological  correlation,  as, 
according  to  experience,  inflammatory  processes  aft'ect  very  commonly  other 
members  of  the  ductless  glandular  system.  Here  we  often  find,  therefore, 
as  we  shall  see  later,  transitions  to  pathological  correlations.  Also  the 
increase  in  function  may  be  produced  experimentally  in  the  pure  form  as,  for 
example,  after  feeding  with  thyroid-gland  substance.     Again,  in  many  cases 


RECIPROCAL    ACTION    OF    THE    DUCTLESS    GLANDS  7 

of  Basedow's  disease  and  of  acromegaly  there  are  no  grounds  for  doubting 
an  increase  in  function  of  the  ductless  gland  affected,  though  even  here  the 
transition  to  pathological  correlations  is  extraordinarily  common. 

I  will  now  quote  some  examples  of  the  physiological  correlations,  con- 
fining myself  chiefly  to  the  investigations  I  carried  out  in  collaboration 
with  Eppinger  and  Rudinger. 

The  total  extirpation  of  the  thyroid  gland  with  careful  avoidance  of  the 
parathyroid  glands — the  electric  excitability  must  show  no  increase  in  con- 
sequence of  the  procedure — calls  forth  a  diminution  of  the  total  processes 
of  metaboHsm.  Let  us  examine  a  little  more  in  detail  the  carbohydrate 
metabolism  in  a  thyroidless  animal.  The  power  of  assimilation  for  carbo- 
hydrates is  increased.  Now,  as  it  has  been  known  that  the  capacity  of  as- 
similation depends  upon  the  functional  breadth  of  the  insular  apparatus  of 
the  pancreas,  we  may  draw  the  conclusion  that  there  must  be  a  relative  or 
an  absolute  increase  of  the  function  of  the  insular  apparatus  of  the  pancreas. 
But  the  extirpation  of  the  thyroid  gland  also  diminishes  the  excitability 


C.  T. 

Fig.   I. — P,  Insular  apparatus  of  the  pancreas;  T,  thyroid;  C.T.,  chromaffin  tissue; 
— ,  inhibition;   -\-,  reinforcement. 

of  the  vegetative  nerves.  For  example,  the  glycosuric  action  of  adrenalin — 
in  addition  to  other  actions,  such  as  the  production  of  a  hyperglobulia — is 
diminished.  As  it  is  known  that  the  excitability  of  the  myoneural  junction 
of  the  sympathetic  nerves  depends  upon  the  activity  of  the  chromaffin  tissue, 
we  may  readily  infer  that  the  activity  of  this  ductless  gland  {i.e.,  the 
chromaffin  tissue)  is  diminished,  whether  it  be  that  the  production  of  adren- 
alin is  diminished,  or  that  the  working  of  this  hormone  in  the  organs  affected 
is  slighter  because  of  the  fact  that  an  otherwise  present  sensitivization  of  the 
organs  fails  to  occur  {Asher  sind  Flack).  A  sensitivization  for  adrenalin  has 
also  been  assumed  as  due  to  the  extract  from  the  posterior  lobe  of  the  hypo- 
physis {Kepinow) . 

After  the  total  extirpation  of  the  pancreas  there  occurs  an  increase  of  all 
metabolic  processes  with  a  high-grade  diminution  of  the  assimilation  hmits 
for  carbohydrates.     In  addition  there  are  indications  of  an  increased  ex- 


8  GENERAL    PART 

citability  of  the  sympathetic  nerves  (Ldici's  reaction,  increased  glycosuric 
action  of  adrenalin).  Therefore  we  conclude  that  there  is  an  increased 
function  of  the  chromaffin  tissue  or  at  least  there  is  an  increased  action  of  the 
circulating  adrenalin.  Again,  in  Addison's  disease,  in  which  the  function 
of  the  chromaffin  tissue  is  primarily  diminished,  we  find  a  heightening  of 
the  assimilation  limits  for  carbohydrates.  We  explain  this  as  due  to  with- 
drawal of  the  inhibition  exercised  by  the  chromaffin  tissue  on  the  insular 
apparatus  and  to  a  secondarily  increased  function  of  the  latter. 

Neu'hurg/i,  Nobel  and  /  have  contributed  a  further  observation.  Peroral 
administration  of  thyroidin  occasions  in  human  diabetes  a  long-continued 
hypertonia.  We  interpret  this  as  the  functional  increase  of  the  chromaffin 
tissue  in  consequence  of  a  heightened  sensibility  of  this  tissue  or  of  its  central 
projection  fields. 

Through  this  anfl  similar  experimental  findings  and  clinical  observations 
the  conclusion  was  drawn  as  to  a  reciprocal  action  between  thyroid,  insular 
apparatus  of  the  pancreas,  and  chromaffin  tissue.  This  is  well  shown  in  the 
accompanying  diagram  (see  Fig.  i). 

As  before  stated,  we  are  not  as  yet  clear  as  to  the  intimate  process  of  such 
physiological  correlations.  This  applies  not  only  to  the  reinforcement 
[Forderung]  but  also  to  inhibition.  We  have  indeed  assumed  that  increased 
activity  of  the  insular  apparatus  inhibits  the  function  of  the  chromaffin 
tissue  or  of  the  thyroid,  and  the  converse.  Another  possibility  consists  in 
the  fact  that  adrenalin  and  the  pancreas  hormone  act  antagonistically  to- 
ward each  other  in  the  liver;  the  one  in  an  acceleratory  manner,  the  other 
in  a  retarding  manner,  upon  the  diastatic  processes;  or  the  one  acts  for  the 
building  up  of  glycogen,  the  other  for  its  splitting  up.  Increased  activity  of  the 
one  would  therefore  disturb  the  balance  between  the  two  ductless  glands.^ 

As  I  have  expressed  in  a  recent  communication,  the  relations  between 
thyroid  and  pancreas  seem  to  me  better  based  and  explained  in  the  following 
way:  Increased  activity  of  the  thyroid  makes  greater  demand  on  the  func- 
tion of  the  insular  apparatus.  If  the  insular  apparatus  does  not  come  up  to 
these  demands,  the  balance  between  both  becomes  disturbed.  This  point 
of  view  is  supported  by  a  series  of  clinical  observations. 

It  is  futile  to  raise  ideas  as  to  physiological  correlation  which  deal  with 
the  question  whether  one  ductless  gland  can  act  compensatorily  for  another. 
Such  an  assumption  depends  upon  entirely  superficial  observation.  Every 
ductless  gland  has  its  specific  function,  although  similar  features  may  enter 
into  the  sum  total  of  activity.  As  this  point  is  of  important  significance,  I 
will  quote  some  examples.  The  extirpation  of  the  hypophysis,  just  as  that 
of  the  thyroid  gland,  brings  about  a  condition  in  which  the  vegetative  func- 
tions are  diminished  (Aschner).  Nevertheless,  a  dog  deprived  of  its  hypo- 
physis looks  otherwise  than  one  deprived  of  its  thyroid,  as  R.  PaltauJ  lays 

'  Exj)eriments  of  Ziiltizcr  and  of  Von  Bdlint  and  Mohuir  point  in  tiiis  direction. 


RECIPROCAL    ACTION    OF    THE    DUCTLESS    GLANDS  9 

stress  on.  Naturally  this  is  also  true  in  a  clinical  sense.  Practically  nobody 
confuses  a  typical  myxedema  with  typical  hypophysial  dystrophy.  The 
extirpation  of  the  parathyroid  glands  increases  the  excitability  of  the  vegeta- 
tive nerves,  extirpation  of  the  thyroid  diminishes  it;  the  mechanism,  however, 
as  I  shall  show  later,  is  different.  It  is  true  that  the  tetany  of  the  parathyro- 
privic  animal  runs  a  milder  course  (after  associated  or  subsequent  thyroidec- 
tomy), because  on  account  of  the  absence  of  the  secretion  of  the  thyroid 
gland  the  excitability  of  the  vegetative  nervous  system  is  diminished,  but 
nevertheless  the  tetany  is  not  thereby  prevented. 

Now,  as  to  the  pathological  correlations!  These  are  furnished  by  the 
ductless  glands'  membership  in  the  same  system.  Diseases  which  affect  one 
gland  often  attack  very  commonly  other  ductless  glands,  or  a  disease  process 
may  affect  simultaneously  several  ductless  glands,  or  the  entire  ductless 
glandular  system.  By  pathological  correlations  I  understand  the  conceal- 
ment, intensification,  or  modification  of  symptoms  due  to  the  alteration  of 
function  of  one  kind  of  ductless  gland  through  the  presence  of  disease  in  an- 
other. This  may  also  be  shown  experimentally.  I  have  already  mentioned 
that  extirpation  of  the  thyroid  gland  diminishes  the  excitability  of  the  vege- 
tative nerves,  while  that  of  the  parathyroids  increases  it.  We  observe  that 
the  glycosuric  action  of  adrenalin,  which  is  diminished  after  extirpation  of 
the  thyroid  gland,  is  not  diminished  on  simultaneous  extirpation  of  the  para- 
thyroid gland  and  may  even  be  somewhat  intensified.  Another  example: 
Extirpation  of  the  thyroid  gland  raises  the  assimilation  limits  for  carbohy- 
drates- and  reduces  the  protein  exchange  during  fasting.  Extirpation  of  the 
pancreas  reduces  the  assimilation  limits  very  strongly  and  increases  the  pro- 
tein exchange  during  fasting.  Simultaneous  extirpation  of  the  thyroid  gland 
and  pancreas  produces  indeed  a  diabetes;  this,  however,  pursues  a  milder 
course  to  the  extent  that  the  increase  of  the  protein  destruction  is  not  so  high 
and  the  diminution  in  weight  does  not  progress  so  rapidly.  Therefore, 
there  has  occurred  a  diminution  of  an  otherwise  increased  metabolism. 

Now  some  examples  from  human  pathology. 

Thyroid  gland  and  the  anterior  lobe  of  the  hypophysis  show  in  many 
respects  much  similarity;  as,  for  example,  in  a  phylogenetic  respect  both  were 
formerly  glands  with  external  secretion.  They  show  similarity  in  morpho- 
logical structure,  and  in  many  respects  also  in  their  physiological  activity. 
For  example,  young  animals  deprived  of  their  thyroid  gland  or  of  their 
hypophysis  remain  backward  in  growth,  show  diminution  of  the  vegetative 
processes,  etc.  Often  both  glands  become  diseased  simultaneously.  In- 
deed, in  acromegaly  the  development  of  a  Basedow's  struma  is  not  unusual, 
and  in  the  later  stages  of  acromegaly  the  thyroid  may  degenerate,  with 
attendant  myxedema  symptoms,  as  Pineles  has  described.  In  the  cretinic 
degeneration  there  is  found  not  uncommonly  both  a  goitrous  degeneration 
of  the  thyroid  gland  and  degeneration  of  the  glandular  hypophysis.     A 


lO  GENERAL    PART 

simultaneous  affection  of  thyroid  gland  and  glandular  hypophysis  is  found 
also  in  multiple  ductless  glandular  sclerosis. 

Another  example  concerns  the  insular  apparatus  of  the  pancreas  and  the 
thyroid.  In  typical  myxedema  the  assimilation  limit  for  carbohydrates  is 
raised.  Now  there  are  individual  cases  of  myxedema  described  in  the  litera- 
ture in  which  alimentary  glycosuria  may  be  obtained,  and  even  indeed  a 
spontaneous  glycosuria  may  be  present  on  ingestion  of  diet  somewhat  richer 
in  carbohydrates  than  ordinarily.  Such  cases  have  been  held  up  to  me  as 
irreconcilable  with  our  theory  as  to  the  reciprocal  actions  of  the  thyroid  gland 
and  pancreas,  but  incorrectly.  In  such  cases  it  may  be  assumed  that 
there  is  a  simultaneous  affection  of  the  insular  apparatus.  I  have  already 
mentioned  that  after  simultaneous  extirpation  of  the  thyroid  gland  and  the 
pancreas  the  oppositely  directed  eft'ect  of  the  absence  of  the  thyroid  on  the 
carbohydrate  metabolism  compensates  for  the  eft'ect  of  the  absence  of  the 
pancreas.  It  is  therefore  fully  comprehensible  that  in  an  aft'ection  of  the 
insular  apparatus  disturbances  in  the  carbohydrate  metabolism  may  occur 
in  spite  of  the  myxedema  that  is  present. 

Finally,  further  example  is  afforded  by  the  pancreas  and  the  suprarenal 
glands.  In  the  cases  of  cirrhose  bronzee  dependent  upon  severe  alcoholism 
there  are  found  extensive  sclerotic  processes  in  the  liver,  the  spleen,  and 
eventually  in  dift'erent  other  organs,  with  simultaneous  deposition  of  a  pig- 
ment that  is  at  first  rich  in  iron  and  later  free  of  iron  (hemosiderosis).  With 
involvement  of  the  pancreas  in  the  sclerotic  process,  diabetes  mellitus 
not  unusually  occurs  (diabete  bronzee).  Now,  observations  have  shown 
that  in  such  cases  the  diabetes  later  disappears,  as  not  rarely  the  cirrhose 
bronzee  involves  also  the  suprarenal  glands  in  the  sclerotic  processes  and  may 
finally  even  bring  about  the  condition  of  symptoms  resembling  Addison's 
disease;  so  that  we  may  readily  draw  the  conclusion  that  the  retrogression  of 
the  diabetic  disturbances  of  metabolism  stands  in  connection  with  a  more 
intense  sclerosing  of  the  suprarenal  glands  that  occurs  later  [in  the  course 
of  the  disease]. 

Question  of  Dysfunction 

The  study  of  the  pathological  correlations  seems  to  me  to  throw  light  on 
the  question  as  to  whether  we  are  justified  in  postulating,  in  addition  to  an 
increase  in  function  and  a  diminution  in  function  of  the  ductless  glands,  also 
a  dysfunction.  1  shall  in  this  book  try  to  explain  the  individual  ductless 
glandular  diseases  exclusively  as  due  to  quantitative  alterations  in  the  duct- 
less glands.  I  know  well  full  that  to-day  this  opinion  is  not  throughout 
the  generally  prevailing  one,  and  I  expect  to  meet  with  opposition.  I  believe, 
however,  that  I  can  at  least  adduce  so  much  evidence  for  my  standpoint 
that  a  certain  justification  for  it  will  not  be  denied. 

As  has  been  previously  stated,  the  physiologico-chemical  basis  of  the 


QUESTION    OF    DYSFUNCTION  II 

hormone  teaching  is  still  insufficient.  Up  to  the  present  only  a  single  hor- 
mone, adrenalin,  has  been  defined  chemically.  A  dysfunction  of  the  chrom- 
affin tissue  would  then  signify  that  a  qualitatively  altered,  faulty,  adrenalin 
is  obtained  from  the  chromaffin  tissue  and  given  off  into  the  blood-path. 
But  every  ground  for  this  opinion  has,  up  to  the  present,  been  lacking.  As 
a  principal  argument  for  dysfunction  is  adduced  the  variability  of  the  clinical 
pictures  that  may  be  expressed  by  the  disease  of  a  definite  ductless  gland. 
The  study  of  the  pathologic  correlations  teaches  us,  however,  that  often  the 
pure  picture  of  a  functional  increase  or  deficiency  may  be  set  aside  and 
concealed  if  other  ductless  glands  become  affected  at  the  same  time. 
Thus  it  not  rarely  happens  that  trophoneuroses  accompany  the  diseases  of 
the  ductless  glands,  the  combination  seeming  to  me  only  a  loose  one.  For  in- 
stance, special  stress  has  been  laid  on  the  observation  that  in  the  later  stages 
of  Basedow's  disease  sometimes  signs  of  myxedema  occur,  while  the  signs  of 
hyperthy'rosis  are  still  present.  In  the  description  of  Basedow's  disease 
I  shall  dwell  at  length  on  these  cases,  and  I  believe  that  in  no  case  is  the  evi- 
dence for  the  existence  of  a  myxedema  absolutely  convincing.  In  common 
with  Newhurgh  and  Nobel,  I  have  further  shown,  in  connection  with  this 
question,  that  the  great  multiplicity  of  syndromes  in  conditions  of  func- 
tional increase  of  a  definite  ductless  gland  are  for  the  most  part  to  be  explained 
through  diversities  of  constitution.  We  have  attempted  to  justify  this 
experimentally.  The  individual  hormones  or  ductless  glandular  extracts 
have  very  different  kinds  of  action  throughout.  As  I  shall  come  to  speak  of 
adrenalin  in  this  connection  later,  I  shall  choose  as  example  at  this  place 
the  thyroid-gland  substance.  By  peroral  administration  of  large  amounts 
of  thyroid-gland  substance,  we  can  see  the  following  symptoms  make  their 
appearance : 

1.  Tachycardia. 

2.  Great  depression  in  the  blood  pressure  from  center  to  the  periphery. 

3.  Increase  of  the  fundamental  exchange. 

4.  Increase  of  the  protein  exchange. 

5.  Increase  of  the  ehmination  of  salts. 

6.  Lowering  of  the  assimilation  for  carbohydrates,  and  finally  spon- 

taneous glycosuria. 

7.  Sweats. 

8.  Mononucleosis. 

9.  Tremor. 

10.  Diarrheas. 

11.  Psychic  agitation,  etc.,  etc. 

Thus  there  are  produced  almost  all  the  symptoms  of  a  Basedow's  disease. 
We  almost  never,  however,  succeed  in  obtaining  all  these  symptoms  in  a 
single  individual,  but  do  note  the  regular  appearance  of  tachycardia  as  the 
cardinal  symptom.     To  this  other  symptoms  group  themselves  to  form  definite 


12  GENERAL    PART 

syndromes;  for  example,  tachycardia,  sweats,  mononucleosis,  or  tachycardia, 
mononucleosis,  tremor,  etc.  We  can  therefore  obtain  in  miniature  almost 
all  the  syndromes  that  we  find  in  cases  of  Basedow's  disease.  As  thyroidin 
is  always  the  same,  the  cause  of  this  dissociation  must  be  ascribed  only  to  the 
various  constitutions  of  the  persons  tested.  The  question  as  to  why  this  is 
so  in  the  individual  case  is  naturally  hard  to  answer,  as  the  sum  of  the  partial 
constitutions  (to  use  an  expression  of  Martius\s)  that  go  to  make  the  total 
constitution  is  enormous.  In  many  respects  it  seems  most  reasonable  in 
experimental  hyperthyroidism  to  seek  the  explanation  in  the  different  reac- 
tion activities  of  the  ductless  glandular  system.  When,  for  example,  we  see 
that  administration  of  thyroid  substance  produces  glycosuria  in  one  in- 
dividual and  in  another  does  not  alter  the  carbohydrate  metabolism,  we 
may  readily  infer  that,  on  account  of  the  known  physiological  correlation 
between  thyroid  and  pancreas,  in  the  first  case  the  insular  apparatus  has  not 
kept  pace  with  the  demands  that  the  hyperthyroidism  has  made  upon  it, 
while  in  the  other  case  the  functional  capacity  of  the  pancreas  is  sufficient. 
In  other  cases  entirely  different  constitutional  factors  appear  more  strongly  in 
the  foreground.  For  example,  in  neuropathic  predisposition,  the  symptoms 
on  the  part  of  the  nervous  system  and  the  mind  occur  more  markedly  and 
have  other  features.  This,  ceteris  paribus,  holds  just  as  good  for  the  [diseases 
due  to]  functional  increases  as  [for  those  due  to]  deficiencies. 

Our  standpoint  as  to  dysfunction  is  important  not  only  theoretically  but 
practically.  If  we  discard  dysfunction,  the  therapeutic  indications  are  much 
clearer.  The  results  of  substitution  therapy  are  thus  readily  made  intelH- 
gible,  and  the  operative  treatment  of  conditions  due  to  hyperfunction 
properly  receives  its  justification  only  in  this  way.  It  appears  to  me  that 
the  study  of  the  pathologic  correlations  is  important  for  the  explanation  of 
many  a  therapeutic  failure.  In  symptoms  due  to  lack  of  a  gland,  a  complete 
result  as  the  consequence  of  substitution  therapy  is  not  to  be  expected  when 
other  parts  of  the  ductless  glandular  system  are  involved  at  the  same  time. 
Perhaps  in  such  cases  more  can  be  achieved  through  combined  organotherapy. 
Pertinent  contributions  in  the  French  literature  appear  to  me  to  be  in  part 
very  optimistic.  A  similar  consideration  of  the  pathological  correlations  is 
perhaps  due  in  the  position  of  the  indications  for  the  operative  treatment  of 
the  hyperfunctional  disease.  One  would  perhaps  take  exception  to  a  resec- 
tion of  the  thyroid  when  at  the  same  time  other  manifestations  are  present 
that  point  to  exhaustion  of  another  ductless  gland,  for  instance,  the  chrom- 
affin tissue.  In  this  connection  still  another  factor  is  important,  namely,  the 
relations  between  the  ductless  glandular  system  and  the  central  nervous 
system.     I  shall  speak  about  this  subject  later. 

Only  a  few  words  yet  as  to  the  intoxicalion  theory  that  plays  so  great  a 
role  in  the  study  of  the  internal  secretions.  The  expression  "poisoning"  is, 
according  to  my  opinion,  well  adapted  in  many  diseases  due  to  hyi)erf unction; 


INFLUENCE    OF    THE    DUCTLESS    GLANDS    ON    THE    GROWTH  1 3 

for  example,  in  Basedow's  disease.  On  this  account  we  do  not  need  to  as- 
sume a  dysfunction,  as  a  normal  secretion,  too,  given  in  excess  to  the  body, 
may  poison  it.  A  fitting  example  is  furnished  by  adrenahn  poisoning.  On 
the  contrary,  I  must  assume  that  no  sufficient  experimental  evidence  is  at 
hand  for  the  detoxication  theory  of  the  disease  due  to  lack  of  secretions;  that 
is,  for  the  assumption  that  poisons  normally  formed  in  the  organism  are 
rendered  nonpoisonous  in  the  ductless  glands,  and  that  they  poison  the  body 
when  the  ductless  glands  are  insufficient.  Even  the  pathogenesis  of  tetany 
may  be  explained  without  the  aid  of  detoxication  theory,  as  we  shall  see  in 
the  chapter  on  the  subject. 

The  great  number  of  works  as  to  the  physiology  and  pathology  of  the 
ductless  glandular  system  that  have  appeared  in  the  last  decade  show  the 
growing  interest  that  physiologists  and  clinicians  take  in  this  subject.  What 
makes  the  subject  so  fascinating  is  the  fact  that  it  allows  us  to  have  what  up 
to  the  present  was  a  scarcely  anticipated  look  into  the  complicated  regulatory 
mechanism  of  the  animal  organism.  In  many  respects  this  influence  is  espe- 
cially true  for  the  influencing  of  the  growth  and  of  the  metabolic  processes. 
But  also  the  development  and  the  activity  of  the  hematopoietic  apparatus 
stand  under  the  control  of  this  ductless  glandular  system;  finally,  the  most 
intimate  relations  exist  between  the  ductless  glandular  system  and  the 
nervous  system,  whereby  practically  all  the  somatic  and  vegetative  functions, 
yes  even  the  mind  itself,  are  brought  within  the  zone  of  influence.  To  de- 
scribe in  detail  this  invasive  activity  of  the  ductless  glandular  system  into 
all  the  vital  processes  does  not  lie  within  the  limits  of  the  task  I  have  set  for 
myself.     1  shall  only  sketch  a  few  points  in  gross. 

Influence  of  the  Ductless  Glands  on  the  Growth 

I  begin  with  the  influence  of  the  ductless  glands  upon  the  growth  and  the 
configuration  of  the  body.  This  influence  is  apparent  and  has  long  been 
known  in  eunuchs  and  through  the  experience  of  breeders  of  animals,  al- 
though exact  experimental  work  in  this  direction  dates  only  from  recent 
years.  It  seems  to  me  most  suitable  for  our  purposes  to  select  certain  better 
studied  types  and  to  sketch  them. 

I.  Loss  or  high-grade  hypoplasia  of  the  sexual  glands  at  an  early  age 
leads  to  tall  growth;  the  skeleton  is  built  slenderly  and  shows  charac- 
teristic proportions  (large  lower  length,  large  span  width,  small  head). 
There  is  found  herewith  a  characteristic  distribution  of  fat  and  faulty  de- 
velopment of  the  secondary  sexual  characters.  The  closure  of  the  epiphy- 
sial junctures,  and  especially  of  those  which  under  physiological  conditions 
close  the  latest,  are  markedly  delayed.  This  is  the  foundation  of  the  char- 
acteristic proportions  and  the  cause  of  the  tall  growth.  (The  assumption  of 
secondary  increase  in  function  of  the  hypophysis,  as  I  shall  treat  in  Chapter 


14  GENERAL    PART 

X,  I  do  not  regard  as  warranted.)  We  may  therefore  assume  that  there  is 
exercised  by  the  sexual  glands,  especially  at  the  time  of  puberty,  an  influence 
upon  the  zone  of  ossification  in  the  sense  of  a  definite  bone  formation.  This 
influence  is  exercised  on  the  part  of  the  interstitial  glands. 

2.  Absence  or  high-grade  diminution  of  the  function  of  the  thyroid  gland 
at  an  early  age  leads  to  dwarf  growth;  that  is,  to  inhibition  of  growth.  The 
skeleton  retains  in  general  the  childish  dimensions.  The  epiphysial  closure 
is  to  a  marked  degree  delayed.  The  fontanelles  remain  open  for  a  long  time, 
the  root  of  the  nose  is  drawn  in,  the  development  of  the  bone-nuclei  is  very 
much  retarded.  The  bones  already  formed  show  a  slight  degree  of  sclerosis. 
The  bones  are  thick.  In  youthful  individuals  with  Graves'  disease  there  is 
found  on  the  contrary  a  shghtly  accelerated  growth  in  the  length,  and  a 
somewhat  premature  closure  of  the  epiphyses.  The  eunuchoid  distribution 
of  fat  is  absent.  The  genitals  remain  backward  in  development,  but  not  so 
markedly  as  in  eunuchoidism.  Under  the  influence  of  the  insufficiency  of  the 
thyroid  gland  the  endochondral  and  periosteal  ossifications  are  to  a  slight 
degree  retarded. 

3.  Absence  of  the  hypophysis  in  early  years  also  leads,  as  clinical  and 
recently,  also,  experimental  observations  show,  to  an  inhibition  of  growth. 
Closure  of  epiphysial  junctures  and  development  of  the  bone-nuclei  are  Hke- 
wise  delayed,  perhaps  not  so  markedly  as  in  the  thyrogenic  inhibition  of 
growth;  this,  however,  is  hard  to  decide,  at  least  in  the  clinical  observations, 
as  the  observations  oh  the  disturbances  do  not  seem  to  deal  with  cases  at 
such  an  early  age.  The  hypoplasia  of  the  genitalia  and  especially  of  the 
interstitial  glands  is  very  much  more  marked,  also  when  the  disturbance  sets 
in  later.  Correspondingly  there  is  found  a  eunuchoidal  distribution  of  fat 
and  even  a  (secondary)  influencing  of  the  body  proportions  which  approxi- 
mate more  or  less  closely  the  eunuchoid  tv'pe. 

In  cases  of  youthful  acromegaly  the  relations  are  very  much  more  com- 
plex. The  t}'pical  cases  appear  to  me,  as  I  shall  treat  of  in  greater  length  in 
Chapter  VI,  to  be  those  with  a  marked  accentuation  of  the  functions  of  the 
interstitial  glands.  We  find  then  premature  closure  of  the  epiphysial  junc- 
tures, more  emphatic  pronunciation  of  the  secondary  sexual  characters, 
and  premature  thickening  of  the  bones  with  exostosis  formation  and  thicken- 
ing of  the  soft  parts.  In  other  cases  we  find,  however,  inhibition  of  develop- 
ment in  the  genital  sphere,  together  with  a  marked  eunuchoidal  tendency 
in  the  proportioning,  with  tall  growth. 

4.  In  disorders  of  h^-perfunction  of  the  sexual  glands,  of  the  suprarenal 
cortex,  or  of  the  epiphysis  in  youthful  life,  we  find  premature  development  of  the 
whole  body,  accelerated  growth  with  potentized  childish  dimensions,  prema- 
ture development  of  the  genitalia,  and  then  laterpremature  epiphysial  closure; 
in  short,  a  transitory  gigantism.  Whether  these  vegetative  disturbances  can 
be  the  direct  outcome  of  those  of  the  organs  mentioned,  or  whether  thev  are 


INFLUENCE    OF    THE    DUCTLESS    GLANDS    ON    THE    GROWTH  1 5 

always  dependent  on  a  primary  or  secondary  increase  in  function  of  the 
suprarenal  cortex,  is  as  yet  uncertain. 

As  to  the  influence  of  the  other  ductless  glands  on  the  growth  and  confor- 
mation of  the  body  as  yet  little  that  is  reliable  is  known.  I  shall  only  men- 
tion that  extirpation  of  the  thymus  glands  leads  to  an  inhibition  of  growth 
that  is  later  compensated.  I  shall  treat  of  this  further  in  the  appropriate 
chapter. 

The  manner  and  means  in  which  the  ductless  glands  affect  the  growth  is 
only  partly  known.  It  may  be  said  with  certainty  that  the  closure  of  the 
epiphyses  and  hence  a  definite  cessation  in  the  normal  growth  occurs  under 
the  influence  of  the  sexual  glands  and  indeed  the  interstitial  glands;  further, 
that  the  development  of  the  bone-nuclei  and  the  growth  in  length  of  the  bones 
is  strongly  influenced  by  the  thyroid  gland  and  the  hypophysis.  I  would 
ascribe  to  the  thyroid  in  this  connection  an  influence  at  least  as  great  as  that  of 
the  hypophysis.  The  influence  of  the  latter  seems  to  be  very  much  over- 
estimated, to  the  extent  that  it  has  been  regarded  as  the  dominating  growth 
center.  The  disturbances  in  growth  produced  by  the  thyroid  differ  im- 
portantly from  those  produced  by  the  hypophysis;  I  would  especially  at- 
tach importance  to  the  fact  that  in  the  thyroidal  growth  disturbances  the 
bones  are  thick  [German  word  "plump"  =  coarse,  thick,  awkward];  in  the 
hypophysoprivic  they  are  slender;  the  contrary  may  be  seen  in  the  increase  of 
function  of  these  glands  in  early  youth.  In  youthful  Basedow's  patients  the 
bones  are  slender;  in  youthful  acromegalics  they  are  thick  and  provided  with 
exostoses,  and,  so  far  as  the  disease  is  not  complicated  with  associated  eu- 
nuchoidism, the  bony  processes  are  thickened.  For  the  overestimation  of 
the  significance  of  the  hypophysis  for  the  growth  in  length  the  Brissaud- 
Meige's  formula  for  gigantism  should  be  held  responsible.  According  to  this 
formula,  gigantism  is  nothing  other  than  an  acromegaly  of  youth.  It  seems 
to  me,  however,  that  in  gigantism,  at  least  in  the  earlier  stages,  there  is  found 
mostly  a  hjrperplasia  also  of  other  ductless  glands,  perhaps  of  the  whole  duct- 
less glandular  system;  and  especially  the  suprarenal  cortex  is  often  hyper- 
plastic and,  according  to  recent  investigations,  may  influence  in  many  ways 
the  clinical  picture  of  gigantism  as  well  as  of  acromegaly.  I  have  pre- 
viously mentioned  that  also  premature  development  can  be  associated  with 
an  increase  of  function  in  this  organ,  perhaps  is  regularly  associated  with  it. 

Although  here,  too,  very  little  is  as  yet  known  and  explained  in  a  satis- 
factory manner  as  to  the  influence  on  the  growth  and  bodily  conformation 
through  the  ductless  glands,  yet  this  influence  is  so  striking  that  we  may 
conclude  that  a  harmonious  development  of  the  body  is  not  possible  without 
orderly  functioning  of  the  ductless  glandular  system.  We  as  yet  know 
nothing  as  to  the  intimate  processes  in  this  kind  of  hormone  action.  Trophic 
influencing  of  the  nervous  system  may  come  into  play  in  many  of  these 
actions,   as  the  symmetry  in  such  formative  influences  seems   to  signify. 


I 6  GENERAL    PART 

Further,  a  specific  influencing  of  the  metaboHc  processes,  for  example  in  an 
athyrosis,  is  to  be  thought  of;  further,  a  modehng  influence  on  the  skeleton 
through  alteration  of  the  muscle  tonus,  etc.,  etc.  It  would,  however,  be 
a  mistake  to  bring  into  relationship  with  the  ductless  glandular  system 
all  variations  and  diminutions  or  increases  in  the  growth  energy  of  the 
protoplasm. 

Influence  of  the  Ductless  Glands  on  the  Regulation  of  Metabolism 

The  ductless  glands  assume  a  still  more  considerable  influence  in  the  regu- 
lation of  metabolism.  I  shall  here  choose  only  a  few  of  the  most  marked 
examples.  First  let  us  consider  the  carbohydrate  metabolism.  The  pan- 
creatic insular  apparatus  governs  the  carbohydrate  assimilation,  for  after 
extirpation  of  the  pancreas  the  glycogen  formation  in  the  liver  and  also 
otherwise  in  the  tissues,  especially  the  muscles,  is  markedly  disturbed.  That 
this  consists  chiefly  in  a  disturbance  of  glycogenesis  seems  to  arise  from  the 
fact  that  on  low-grade  insulhciency  of  the  pancreas  the  disturbances  first 
become  manifest  only  on  alimentary  overloading,  while  otherwise  the  regu- 
lation of  the  carbohydrate  metabolism  is  proceeding  normally.  Then  an 
increased  sugar  production  occurs  first  in  the  high  grades  of  the  disturbance, 
for  now  there  occurs  also  on  fasting — hence,  with  full  exclusion  of  the  ali- 
mentary influence — hyperglycemia  and  glycosuria. 

On  the  other  hand,  the  mobilization  of  glycogen  seems  to  stand  chiefly 
under  the  influence  of  the  chromafiin  tissue,  for  artificially  induced  hyper- 
adrenalinemia  (through  subcutaneous  injection  of  adrenalin  or  through 
sugar  puncture)  brings  about  a  rapid  melting  down  of  the  glycogen  present 
in  the  liver  and  muscles,  and  perhaps  also  an  increased  combustion  of  sugar 
(for  after  injection  of  adrenalin  we  saw  a  rise  of  the  respiratory  quotient). 
Thereby  occurs  hyperglycemia  and  eventually  glycosuria;  after  extirpation 
of  the  suprarenals  or  in  Addison's  disease  there  exists,  on  the  contrary, 
a  hypoglycemia. 

Both  the  pancreatic  insular  apparatus  and  the  chromafiin  tissue  are  to  be 
regarded  as  most  important  regulators  of  the  carbohydrate  metabolism, 
and  we  must  add  to  them  as  a  regulator  the  thyroid  gland;  for,  as  previously 
mentioned,  in  typical  myxedema  the  assimilation  limits  are  raised,  and  in 
Basedow's  disease  or  in  artificial  thyroidism  they  are  not  rarely  reduced,  in 
some  cases  to  such  an  extent  that  spontaneous  glycosuria  occurs.  As  I  here 
again  emphasize,  the  thyroid  gland  seems  to  influence  especially  the  pan- 
creatic insular  apparatus  or  the  hormone  produced  by  it,  as  here  the  ali- 
mentary factor  is  so  prominent.  A  similar  regulatory  influence,  although 
probably  not  such  a  strong  one,  seems  to  proceed  from  the  hypophysis;  I 
shall  speak  of  this  in  the  appropriate  chapter. 

So  far  as  the  protein  metabolism  is  concerned,  we  have  known  for  some 


INFLUENCE  OF  THE  DUCTLESS  GLANDS  ON  THE  REGULATION  OF  MET.ABOLISM    I  7 

time  that  the  thyroid  gland  influences  it  enormously.  In  Basedow's  disease 
the  protein  requirements  are  increased;  the  patient  must  ingest  more  protein 
if  he  does  not  wish  to  use  up  the  protein  constituents  of  his  body.  In 
myxedema  the  protein  requirements  are  abnormally  low.  In  hypophysial 
and  suprarenal  diseases  these  disturbances  in  the  protein  economy  are  not  so 
distinctly  prominent.  Also  the  severe  diabetic  ordinarily  has  no  heightened 
protein  requirements.^ 

From  these  examples  it  will  be  seen  that  the  regulatory  influence  of  indi- 
vidual ductless  glands  on  the  dift'erent  metabohc  processes  is  to  a  great  extent 
specific.  While  pancreas  and  chromaflin  tissue  govern  the  carbohydrate 
metaboHsm,  the  thyroid  gland  is  especially  important  for  the  protein  meta- 
bolism. For  the  calcium  metabohsm  the  function  of  the  parathyroid  would 
seem  to  be  of  especial  importance,  as  in  tetany  the  assimilation  of  calcium  in 
the  nervous  system  seems  to  be  disturbed,  although  also  other  ductless  glands 
would  seem  to  take  a  part  in  the  regulation  of  calcium  metabohsm.  Thus 
the  thymus  gland  seems  to  be  of  importance  for  the  assimilation  of  calcium 
in  young  bones.  Administration  of  thyroid-gland  substance  or  of  extracts 
of  the  posterior  lobe  of  the  hypophysis  increases  chiefly  the  ehmination  of 
calcium ;  adrenahn  increases  that  of  potassium  and  sodium,  while  the  ehmina- 
tion of  calcium  is  restricted.  The  significance  of  these  experiments  for 
clinical  medicine  is  not  as  yet  clear. 

The  influence  of  ductless  glands  on  the  purin  metabolism  has  as  yet  been 
investigated  but  httle.  The  observations  that  in  acromegaly  the  endogenous 
factor  of  the  uric-acid  ehmination  is  raised,  that  in  hypophysial  dystrophy  it 
may  lie  strikingly  low,  and  that  also  the  exogenous  factor  may  show  oppo- 
sitely directed  alterations,  and  that,  further,  alterations  of  purin  metabolism 
also  occur  in  the  thyroid-gland  diseases,  as  I  shall  show  in  Chapter  II.  make 
probable  the  regulatory  influences  of  the  ductless  glands  on  the  purin  met- 
abohsm. I  must  not  oft'-hand  make  any  statement  as  to  whether  the 
problem  of  gout  will  be  elucidated  by  such  investigation. 

The  study  of  the  respiratory  gaseous  exchange  has  furnished  a  deep  insight 
mto  the  regulation  of  metabohsm  in  the  ductless  glandular  diseases.  Here, 
too,  I  win  hmit  myseh  to  certain  important  facts.  In  Basedow's  disease  the 
fundamental  exchange  is  increased.  In  thyroprivic  or  spontaneous  myxe- 
dema the  fundamental  exchange  and  the  caloric  requirements  are  reduced. 
In  acromegaly  a  distinct  rise  of  the  fundamental  exchange  is  present  only 
when  symptoms  of  Basedow's  disease  are  present  at  the  same  time.  In 
hypophysial  dystrophy  the  fundamental  exchange  is  reduced  only  in  espe- 
cially severe  cases.  In  failure  of  the  sexual  glands  the  reduction  of  the 
fundamental  exchange  is  still  a  moot  question  and  if  present  is  but  shght. 

1  Also  qualitative  alterations  of  the  protein  metabolism  are  observed  in  ductless  glandular 
diseases;  in  tetany,  for  example,,  there  is  a  heightening  of  the  ammonia,  amino-acid.  and  pol\-peptid 
fractions. 


GENERAL   PART 


Investigations  of   the  metabolism  in  premature  development  as  the  result 
of  suprarenal  cortical  sexual  glandular,  and  epiphysial  tumors  have  not  as 
yet  been  made.     In  severe  diabetes  melhtus,  as  will  be  told  about  in  detail  in 
Chapter  XIII,  the  caloric  production  in  the  rest-fasting  experiments  is  not 
essentially  increased;  the  caloric  and  oxygen  requirements  are  increased, 
correspondingly  to  the  loss  of  sugar  and  of  ketone  bodies.     According  to 
the  investigations  up  to  the  .present,  a  considerable  influence  on  the  funda- 
mental exchange  is  to  be  attributed  only  to  the  thyroid  gland.     It  seems 
to  me,  however,  that  for  a  correct  appreciation  of  the  influence  that  the  duct- 
less glands  exercise  on  the  metabohc  processes  and  nutritional  conditions, 
it  is  just  as  important  that  we  consider  the  endogenous  factors  as  well  as  the 
exogenous  factors.     By  fundamental  exchange  we  mean,  as  is  known,  the 
amount  of  the  carbonic-acid  production  and  of  the  oxygen  requirements,  or 
of  the  heat  production,  on  ruling  out  of  digestion  and  muscular  work.     If 
we  calculate  the  fundamental  exchange  per  kilogram  of  body  weight,  we 
find  in  (grown)  small  and  thin  individuals  higher  values  than  in  (grown) 
large  and^fat  individuals.     In  youthful  individuals  the  fundamental  exchange 
is  relatively  larger  than  in  adults.     In  the  small  individuals  the  variations  to 
which  it  is  subject  are  ordinarily  only  very  sUght.     The  fundamental  ex- 
change is  a  measure  for  the  work  that  in  a  resting  fasting  organism  is  per- 
formed by  the  heart,  the  glands,  the  nervous  system,  etc.,  including  that 
which  is  furnished  by  a  certain  muscular  tonus  that  cannot  be  excluded. 
That  the  thyroid  enormously  influences  the  fundamental  exchange  may  be 
readily  understood  when  we  consider  that  in  Basedow's  disease  the  organs 
are  in  a  condition  of  marked  excitement,  while  in  myxedema  the  vegetative 
functions  are  markedly  reduced.     A  certain  influencing  of  the  fundamental 
exchange  is  to  be  expected  also  on  the  part  of  the  other  ductless  glands  as 
they  too  influence  the  vegetative  nervous  system  in  manifold  ways,  so  far 
as  its  condition  of  irritabihty  is  concerned,  even  if  their  influence  does  not 
cause  such  distinct  effects.     But  also  the  exogenous  factor  of  the  exchange 
is  influenced  by  the  ductless  glands  more  or  less  pronouncedly.     I  have 
reference  to  the  unrest  and  mental  irritability  of  Basedow's  disease  and  to  the 
apathy  and  lack  of  interest  of  the  myxedemic.     In  tetany  we  find  in  addition 
to  the  increase  in  the  vegetative  functions  also  an  extraordinary  influencmg 
of  the  exogenous  factors  through  the  fibrillary  twitchings  and  through  the 
spasms.     Also  as  far  as  the  sexual  glands  are  concerned  does  an  exogenous 
factor  come  into  play;  for  instance,  in  eunuchs  there  are  absent  the  stimulus 
to  motion  and  the  animation  of  the  normal  man.     All  these  are  factors  that 
are  of  great  importance  for  the  regulation  of  the  total  exchange  and  for  the 
condition  of  nutrition. 

Even  more  significant  appears  to  me  the  following  circumstance:  That  a 
normal  grown  man  retains  the  same  bodily  weight  for  years  depends  on  a 
correct  relation  between  assimilation  and  dissimilation  assured    by  such 


INFLUENCE  OF  THE  DUCTLESS  GLANDS  ON  THE  REGULATION  OF  METABOLISM      IQ 

different  factors  as  appetite,  impulse  for  movements,  etc.  On  these  processes 
the  ductless  glands  have  a  considerable  influence.  We  can  with  great  prob- 
ability, as  we  shall  see  later,  divide  the  hormones  into  anabolic  and  catabolic 
(retarding  and  acceleratory,  or  assimilatory  and  dissimilatory).  An  im- 
portant anabolic  hormone  is,  for  example,  the  pancreas  hormone,  as  it  is  very 
important  for  the  carbohydrate  assimilation  and,  as  I  am  inclined  to  assume, 
also  for  the  fat  assimilation.  This  fact  also  makes  comprehensible  an  in- 
fluence of  the  ductless  glandular  system  upon  the  regulation  of  the  total  ex- 
change (not  the  caloric  production  alone).  A  fattening,^  that  is,  a  significant 
increase  in  the  assimilatory  processes,  would  only  then  be  possible  when  the 
ability  for  it,  that  is,  a  certain  breadth  of  function  of  the  ductless  glands  in 
question,  is  present,  otherwise  the  organism  would  protect  itself  against  the 
increased  supply  of  food.  This  seems  to  throw  some  light  on  the  obesity 
associated  so  commonly  with  certain  ductless  glandular  diseases.  The  con- 
sideration of  the  fundamental  exchange  alone  would  not  carry  us  to  the  goal, 
for  it  is  very  well  conceivable  that  the  fine  mechanism  of  regulation  between 
assimilation  and  dissimilation  is  disturbed  without  an  alteration  of  the 
activity  of  the  vegetative  organs  to  such  an  extent  as  to  influence  the  funda- 
mental exchange.  Only  in  diseases  in  which  the  diminution  of  the  funda- 
mental exchange  is  quite  clear,  for  instance  in  myxedema,  must  there  be 
added,  if  obesity  is  to  develop,  a  disturbance  in  the  relation  between  assimi- 
lation and  dissimilation,  as  otherwise  the  ingestion  of  nutrition  would  simply 
diminish  with  the  lessened  need. 

Also  in  those  ductless  glandular  diseases  that  according  to  experience  are 
associated  with  emaciation  must  there  be  present  a  similar  disturbance  of 
the  mechanism  of  regulation,  although  in  the  opposite  direction.  The  increase 
in  the  fundamental  exchange  in  Basedow's  disease  can  otherwise  be  vitiated 
by  corresponding  increased  ingestion  of  food.  Here  indeed  the  relations  are 
very  much  more  complicated,  as  the  ingestion  of  much  food  may  be  made 
difiicult  through  vomiting  or  through  diarrhea.  It  seems  to  me,  however, 
that  this  explanation  is  not  sufficient  for  all  cases.  We  sometimes  see  indeed 
in  this  very  Basedow's  disease  a  paradoxical  relation;  in  spite  of  the  per- 
sistence of  Basedow's  disease,  an  obesity  can  develop  after  initial  wasting,  and 
some  have  seen  in  this  obesity  evidence  for  a  dysfunction  of  the  thyroid  gland. 

It  seems  to  me  very  likely  that  in  such  cases,  in  spite  of  persistence  of  an 
increased  dissimilation,  the  assimilatory  processes  on  account  of  a  gradual 
developing  hyperfunction  of  the  pancreas,  win  the  upper  hand.  On  the 
other  hand,  emaciation  may  enter  in  on  account  of  primary  disturbance  of 
assimilation,  as  is  the  case  in  severe  diabetes  mellitus;  here  the  gross  exchange 
is  increased,  the  production  of  calories  not  however  increasing. 

Finally  there  must  be  ascribed  to  the  ductless  glandular  system  an  influ- 
ence on  the  heat-regulation  of  the  animal  organism.     These  disturbances  of 

1  Increase  in  weight  due  to  feeding  [Mastung]. — Editor. 


20 


GENERAL    PART 


the  heat  regulation  occur  most  commonly  and  most  pronouncedly  in  diseases 
of  the  thyroid  gland.     In  myxedema  the  bodily  warmth  often  sinks  far  below 
the  normal;  in  Basedow's  disease  hyperthermia  is  not  rare.     In  the  one  the 
vegetative  functions  are  diminished,  in  the  other  increased;  the  diminished  or 
ina-eased  heat  production  cannot,  however,  alone  be  the  cause.     There  must 
occur  in  addition  other  sorts  of  disturbances,  especially  in  the  mode  of  action 
of  the  vessels  of  the  skin  or  in  the  vegetative  nervous  system,  changes  that 
I  shall  not  go  into  here  on  account  of  their  complexity.     On  the  ground  last 
mentioned,  it  is  well  also  to  ascribe  to  the  chromaffin  tissue  an  important 
role  in  the  regulation  of  heat,  for  adrenalin,  as  may  readily  be  demonstrated 
experimentally,  through  contraction  of  the  vessels  of  the  skin  and  prevention 
of  the  perspiration  may  lead  transitorily  to  a  significant  hyperthermia,  even 
with  shivering.     Also  the  hypophysis  seems  to  enter  into  the  regulation  of 
temperature  on  account  of  its  influencing  the  vegetative  nervous  system;  to 
this  statement  points  the  fact  that  in  hypophysial  dystrophy  the  temperature 
always  is  instituted  at  an  abnormally  low  level.     I  content  myself  with  these 
few  examples;  the  intimate  relation  of  the  ductless  glands  to  the  vegetative 
nervous  system,  which  I  shall  speak  about  later,  furnishes  obvious  explana- 
tion.    The  same  holds  true  for  the  influencing  of  the  icater  economy;  retention 
of  water  in  myxedema,  with  throwing  off  of  water  in  this  condition  by  the  use 
of  thvroidin.  polvuria  in  the  "hypertonic  diathesis,"  diabetes  insipidus  in 
individuals  with  disease  of  the  hypophysis,  diabetes  decipiens  or  high-grade 
polyuria  in  diabetes  mellitus.  are  all  questions  which  have  as  yet  been  very 
little  investigated  and  the  study  of  which  represents  many  results. 

Embryology  of  the  Ductless  Glandular  System 

Before  I  attempt  to  group  the  blood-glands  according  to  their  functions,  I 
should  like  to  sav  a  few  words  as  to  the  embryology  of  the  ductless  glandular 
system.  It  is  a  shame  that  this  subject  has  to  the  present  been  somewhat 
neglected  by  the  embryologists.  All  three  germinal  layers  contribute  to  the 
structure  of  the  ductless  glandular  system.  According  to  the  contributions 
that  I  have  found  in  the  literature,  it  seems  to  me  that  the  following  grouping 

is  possible: 

The  chromaflin  tissue  is  of  neuroectodermal  origin. 

The  posterior  lobe  of  the  hypophysis  is  also  of  neuroectodermal  origin. 
The  pars  intermedia  is  also  of  ectodermal  origin.  It  is  questionable, 
however,  whether  the  pars  intermedia  develops  from  the  anterior  or 
the  posterior  lobe.     In  the  latter  case  it  would  be  of  neuroectodermal 

origin. 
The  anterior  lobe  of  the  hypophysis  develops  from  an  extrusion  of  the 
dorsal  wall  of  the  ectodermal  primary  mouth  cavity  where  it  passes 
over  into  the  entodermal  head-gut. 


EMBRYOLOGY    OF    THE    DUCTLESS    GLANDULAR    SYSTEM  21 

The  middle  lobe  of  the  thyroid  gland  develops  from  the  ventral  wall  of  the 
entodermal  head-gut,  the  lateral  lobes  apparently  in  part  from  the 
ventral  wall  of  the  fourth  pharyngeal  pouch.  The  anterior  lobe  of 
the  hypophysis  and  the  thyroid  gland  are  phylogenetically  older  struc- 
tures and  were  formerly  glands  with  external  secretion  that  poured 
their  secretions  into  the  intestines. 
The  parathyroid  glands  are  of  entodermal  origin  and  develop  from  the 

dorsal  wall  of  the  third  and  fourth  pharyngeal  pouches. 
The  thymus  gland  is  also  of  entodermal  origin  and  develops  from  the 

ventral  wall  of  the  third  pharyngeal  pouch. 
The  pancreatic  insular  apparatus  develops  from  an  extrusion  from  the 
pancreatic   excretory   ducts    and    according    to    Weichselhaum   is    of 
entodermal  origin. 
The  suprarenal  cortex  comes  from  the  epithelium  of  the  body  cavity 

and  is  of  mesodermic  origin. 
The  sexual  glands  develop  from  a  neighdoring  site  of  the  celomic  epithe- 
lium and  are  therefore  also  of  mesodermal  origin;  this  is  generally 
assumed  to  be  true  of  the  interstitial  cells,  while  the  glands  of  genera- 
tion, according  to  the  views  of  many  authors,  develop  directly  from 
the  primordial  cells.     The  cells  of  the  suprarenal  cortex  and  the  cells 
of  the  interstitial  glands  show  a  certain  morphological  similarity. 
The  epiphysis  develops  from  an  extrusion  of  the  roof  of  the  third  ventricle; 
it  is  therefore  in  part  of  neuroectodermal  origin;  in  a  clinical  respect 
it  shows  a  certain  relationship  with  the  interstitial  glands  and  the 
suprarenal  cortex,  so  that  we  can  believe  that  it  is  in  part  of  meso- 
dermic origin. 
Hence  we  may  group  the  ductless  glands,  according  to  their  origin  from 
the  germinal  layers,  into  those  of  neuroectodermal  origin  (chromaffin  tissue, 
posterior  lobe  of  the  hypophysis),  those  of  ectodermal  origin  (anterior  lobe 
of  the  hypophysis),  endodermal  origin  {a)  from  the  head-gut  (thyroid),  {h) 
from  the  branchial  derivatives   (parathyroid  glands,   thymus  gland),   and 
finally  those  of  mesodermal  origin  (suprarenal  cortex,  interstitial  glands, 
pancreatic  insular  apparatus) .     The  glands  of  generation  seem,  on  account  of 
their  development  from  the  original  primordial  cells,  to  take  a  special  place. 
Although  this  grouping  is  incomplete,  still  it  seems  to  me  that  important 
analogies  may  be  derived  from  it.     It  is  striking  that  the  posterior  lobe  of  the 
hypophysis  (and  pars  intermedia?)  and  chromaffin  tissue,  the  active  prin- 
ciples of  which,  adrenalin  and  pituitrinum  infundibulare,  show  a  certain 
similarity  in  their  action,  are  both  of  neuroectodermic  origin,  and  that  the 
anterior  lobe  of  the  hypophysis  and  the  thyroid  gland,  whose  relationship 
in  a  physiological  and  pathological  sense  has  been  many  times  referred  to, 
show  phylogenetically  a  certain  relationship  in  that  formerly  they  wxre  both 
glands  with  an  external  secretion.     Finally,  it  is  striking  that  the  interstitial 


2  2  GENERAL    PART 


glands  and  the  suprarenal  cortex,  which  are  both  of  such  importance  for  the 
development  of  the  secondary  sexual  characters  and  stand  in  immediate 
relation  to  premature  development,  both  develop  from  the  celomic  epithelium. 
From  this  standpoint  it  would  be  interesting  to  see  whether  in  eunuchs  the 
suprarenal  cortex  is  not  hypoplastic.  I  am  well  aware  that  this  grouping  of 
the  ductless  glands  is  associated  with  much  that  is  speculative,  but  never- 
theless it  seems  to  me  that  their  study  in  this  direction  is  of  practical  value. 

Grouping  of  the  Ductless  Glands 

Let  us  now  attempt  a  classification  of  the  ductless  glands  according  to 
their  physiological  actions.     I  first  attempted  such  a  classification  four  years 
ago,  in  which  I  dift'erentiated  acceleratory  and  retarding  hormones.     This 
dift'erentiation  was  founded  on  observations  as  to  the  in  many  respects  an- 
tagonistic influencing  of  the  metaboHc  processes  through  the  hormones  or 
diKtless  glandular  extracts.     Biedl  later  used  the  terms  dissimilatory  and 
assimilatory  for   them.     We  can  also  say  cataboHc  and  anabohc.     This 
division  cannot  be  carried  out  for  the  totahty  of  the  ductless  glands,  yet  it 
seems  to  me  one  well  adapted  for  its  purpose.     I  quote  the  following  examples : 
The  hormone  of  the  thyroid  gland  we  may  regard  with  full  right  as  ac- 
celeratory or  dissimilatory  or  catabolic.     As  far  as  we  know  its  actions, 
it  quickens  metaboKsm  and  increases  excitability.     That  in  absence  of  the 
thyroid  in  early  youth  growth  and  assimilation  remain  behind  does  not  seem 
to  me  to  speak  against  this  assumption,  for  the  arrest  in  growth  is  to  be  re- 
garded only  as  the  eft'ect  of  serious  inhibition  of  all  metaboHc  processes. 

Also  the  hormone  of  the  chromaffin  tissue  is  of  pronounced  acceleratory 
or  cataboHc  action.  It  increases  the  excitabihty  of  the  sympathetic  nerves- 
decomposes  glvcogen,  increases  the  respiratory  metaboHsm.  etc.  (the  more 
intense  formation  of  glycogen  in  the  course  of  a  chronic  adrenaHnizing  I 
regard  as  only  a  secondary  one,  through  compensatorily  increased  activity 
of  the  pancreatic  insular  apparatus). 

Again,  the  posterior  lobe  of  the  hypophysis  belongs  to  this  group  of  duct- 
less glands,  at  least  we  must  regard  the  actions  of  the  pituitrinum  infundi- 
bulare  as  pronouncedly  cataboHc  or  dissimilatory. 

To  this  group  we  may  oppose  the  glands  with  retardative  or  anabolic 
or  assimilatory  hormones.  To  the  latter  belong  the  pancreatic  insular 
apparatus,  that  controls  the  building  up  of  glycogen  and  also  the  assimilation 
of  fat,  and  diminishes  the  excitability  of  the  sjmipathetic  nerves  {Ldwi); 
further  the  parathvroid  glands,  that  probably  assist  the  assimilation  of  cal- 
cium in  the  ganglion-cells  and  at  the  same  time  reduce  their  excitability. 
Both  work  assimilatory  and  excitability-diminishing,  each  however  in  a 
specific  way;  cataract  formation  may  accompany  deficiency  of  either. 

Probablv  to  this  group  belongs  also  the  anterior  lobe  of  the  hypophysis, 


DUCTLESS    GLANDS    AND    NERVOUS    SYSTEM 


23 


the  extract  from  which  reduces  the  fundamental  exchange  and  the  func- 
tional increase  of  which  brings,  about,  as  is  known,  an  abnormal  growth 
energy  in  the  bones  and  soft  parts.  Further  I  might  here  include  the  inter- 
stitial glands,  as  they  influence  the  ossification  of  the  epiphysial  junctures, 
the  growth  of  the  larynx,^  etc. 

I  might  express  the  opinion  that  the  generative  glands  on  the  contrary 
belong  to  the  catabolic  group,  as  in  the  inhibitions  of  growth  that  occur  after 
removal  of  the  interstitial  glands  as,  for  example,  by  X-ray,  only  the  genera- 
tive glands  are  damaged;  furthermore,  we  shall  see  in  the  chapter  on  the 
sexual  glands  that  in  the  premenstrual  period  in  women  all  life  processes  are 
increased  when  the  follicle  ripens;  it  is  probable  that  in  man,  too,  tonic  ex- 
citability-increasing influences  proceed  from  the  generative  apparatus. 

Thymus  gland  and  epiphysis  probably  belong  to  the  anabolic  group. 

If  this  classification,  which  I  regard  as  speculative,  is  confirmed  by  further 
investigation,  it  would  lead  to  a  result  that  appears  to  me  to  be  very  sig- 
nificant. As  is  known,  the  ductless  glands  are  for  the  most  part  arranged  in 
the  organs  in  pairs.  It  would  then  be  seen  that  the  pairs  regularly  belong  to 
different  groups.     This  is  well  shown  in  the  accompanying  diagram. 


Acceleratory  group 
(catabolic-dissimilatory) 


Retardative  group 
(anabolic-assimilatory) 


Germinal  layer 


Ductless  gland 


Ductless  gland 


Germinal  layer 


Fore-gut 

Thyroid  gland 

Parathyroid 

Pharyngeal  pouch 

Xeuroectodermal 

Posterior  lobe  of 

Anterior  lobe  of 

Ectodermal 

hypophysis 

hypophysis 

Neuroectodermal 

Chromafi&n  tissue 

Suprarenal  cortex 

Mesodermal 

Primordial  cell 

Glands  of  generation 

Interstitial  glands 

Mesodermal 

Relation  between  the  Ductless  Glandular  System  and  the  Nervous  System 

I  finally  consider  the  relations  between  the  ductless  glandular  system  and  the 
central  nervous  system.  The  most  recent  years  have  furnished  an  abundance 
of  observations  and  ideas  just  in  this  direction,  but  these  observations  and 
ideas  are  still  very  unclear  and  contradictory;  so  that  a  concise  consideration 
of  this  subject  is  hardly  possible  without  strong  subjective  coloring. 

I  shall  not  consider  more  intimately  here  the  manifold  reciprocal  influ- 
ences that  are  already  furnished  by  the  spatial  relationship  between  many  of 
the  ductless  glands  and  the  nervous  system  (for  example  pressure  action  on 

1  Novak  has  quoted  just  the  sexual  glands  as  an  example  to  show  that  we  are  not  yet  prepared 
for  a  division  into  an  acceleratory  and  retardative  group.  He  says:  If  after  the  removal  of  a 
sexual  gland  we  cause  an  increase  in  growth  and  at  the  same  time  find  a  decrease  in  beard  forma- 
tion and  inhibition  in  the  growth  of  the  larynx,  is  then  the  gland  growth-inhibiting  or  growth- 
increasing? 

If,  however,  we  regard  the  increased  growth  only  as  a  result  of  the  delayed  epiphysial  closure, 
we  find  that  all  effects  of  the  removal  of  the  interstitial  glands  in  youth  are  growth-inhibiting. 


24  GENERAL    PART 

the  mid-brain  by  hypophysial  and  epiphysial  tumors,  and  of  brain  tumors  on 
the  hypophysis  and  epiphysis). 

A.  Influence  of  the  Ductless  Glandular  System  on  the  Nervous  System 

Very  significant  is  the  influence  of  the  ductless  glandular  system  on  the 
psychical  and  mental  functions.  This  subject  has  been  dealt  with  very  often 
in  recent  years,  for  instance,  by  Laignel-Lavastine,  Bauer,  Marburg,  Miinzer, 
and  others;  and  recently  a  considerable  study  has  been  published  on  the 
subject  by  v.  Frankl-Hochwart. 

I  refer  to  the  alteration  in  character  that  is  almost  always  associated  with 
the  development  of  Basedow's  disease;  to  the  psychical  irritability,  the  incli- 
nation to  irascibility,  the  manic-euphoristic  attitude  of  patients  with  Base- 
dow's disease;  to  the  apathy  and  the  lack  of  interest  of  the  myxedematous; 
to  the  characteristic  quiet  mental  attitude  in  hypophysial  dystrophy,  and  the 
feeling  of  mental  want  of  strength  in  those  suffering  with  Addison's  disease; 
to  the  depressive  attitude  of  the  tetany  patient,  and  finally  to  the  profound 
influence  that  the  ripening  of  the  sexual  glands  at  the  time  of  puberty  or 
the  loss  of  function  of  the  sexual  glands  in  castrates  exercises  on  the  psyche. 

The  relations  of  the  ductless  glandular  system  to  the  vegetative  nervous 
system,  as  we  shall  see  later,  are  not  only  important  for  the  pathogenesis  of 
the  ductless  glandular  diseases,  but  they  possess  also  a  great  practical 
interest  through  the  fact  that  in  many  ductless  glandular  diseases  they 
simplify  the  solution  of  the  individual  symptom-complexes  in  many  respects. 
These  relations  are  of  two  kinds: 

1.  The  ductless  glands  themselves  are  vegetative  organs.  They  are  sup- 
plied by  vegetative  nerves  and  possess,  therefore,  central  projection 
fields.  Thus  the  function  of  the  ductless  glands  is  in  great  measure 
regulated  by  the  nervous  system. 

2.  The  ductless  glandular  system  influences  the  excitability  of  the  vege- 
tative nervous  system  by  the  hormones  that  it  gives  off  to  the  circula- 
tion. At  least  this  has  been  ascertained  with  certainty  with  regard 
to  adrenahn,  and  is  in  probability  true  of  the  other  ductless  glandular 
hormones.  I  shall  take  up  this  point  first.  But  before  this  I  wish  to 
say  something  as  to  the  anatomy  and  physiology  of  the  vegetative 
nervous  system. 

As  is  known,  the  vegetative  nervous  system  supplies  chiefly  the  organs 
with  smooth  muscle  fibers.  In  its  function  it  is  partially  independent,  in 
great  degree,  of  the  central  nervous  system.  While  the  somatic  or  animal 
nerves  pass  uninterruptedly  from  the  central  nervous  system  to  their  organs 
of  supply,  the  vegetative  nerves  are  always  interrupted  in  the  vegetative 
ganglia.  We  hence  distinguish  preganglionic  and  postganglionic  vegetative 
neurons.     Langley  divides  the  vegetative  nervous  system  into  two  groups, 


DUCTLESS    GLANDS    AND    NERVOUS    SYSTEM  25 

according  to  anatomical  relations,  into  the  cranio-sacral  and  the  sym- 
pathetic groups.  He  terms  the  whole  vegetative  nervous  system  autono- 
mous, the  group  of  the  cranio-sacral  autonomous  nerves  parasympathetic, 
the  other  group  sympathetic.  The  Viennese  authors,  who  have  busied 
themselves  much  with  this  question,  call  the  cranio-sacral  autonomous  nerves 
without  further  ado  autonomous,  hence  distinguishing  between  autonomous 
and  svmpathetic  nerves.  This  terminology  has  secured  a  large  foothold  in 
the  German  literature.  The  disturbance  in  these  two  groups  depends  upon 
an  extensive  difference  not  only  in  their  anatomical  relations,  but  also  in 
their  physiological  behavior.  The  action  of  both  groups  on  the  organs 
they  affect  is  in  great  part  an  antagonistic  action.  While,  for  example,  the 
sympathetic  accelerator  nerve  accelerates  heart  action,  heart  action  is 
slowed  by  the  autonomous  vagus  nerve.  While  the  sympathetic  splanchnic 
nerves  inhibit  the  peristalsis  of  the  intestine,  this  is  reinforced  through  irrita- 
tion of  the  autonomous  vagus.  The  following  scheme,  which  is  taken  from 
the  experimental  pharmacology  of  H.  H.  Meyer  and  R.  Gottlieb,  shows  these 
relations  in  a  manner  that  may  be  readily  understood  (p.  26). 

The  two  groups  also  are  different  in  a  most  noteworthy  manner  in  their 
behavior  toward  certain  pharmacological  agents.  Indeed  there  has  been 
based  on  this  dift"erence  a  pharmacologic  test  of  function  that  should  furnish 
evidence  as  to  the  condition  of  excitability  of  the  vegetative  nerves.  As  it  is 
also  used  in  afi'ections  of  the  ductless  glands  I  shall  here  briefly  detail  the  most 
important  facts. 

Nicotine  shows  a  specific  affinity  for  all  vegetative  nerves,  but  only  for  the 
preganglionic  fibers  interrupting  conduction  in  these  fibers. 

Adrenalin  acts  as  a  stimulant  to  the  myoneural  junction  of  the  sympa- 
thetic nerves  in  all  their  organs  of  supply,  and  indeed  is  furthering  or  inhibi- 
tory according  as  the  activity  of  the  organ  of  supply,  is  furthered  [fordern]  or 
inhibited  by  electrical  stimulations.  Only  the  sweat-glands  are  not,  when 
the  doses  are  not  too  large,  influenced  by  adrenalin.  On  the  contrary,  ergotin 
shows  a  specific  affinity  for  the  furthering  sympathetic  fibers,  while  the  in- 
hibitory fibers  remain  unaffected. 

On  the  contrary,  pilocarpine,  muscarine,  physostigmine,  and  cholin  act 
as  stimulants  on  all  the  autonomous  nerves,  but  only  the  sweat-glands  in- 
nervated by  the  sympathetic  are  energetically  stimulated  by  these  agents. 
Picrotoxin  acts  similarly,  but  with  a  central  point  of  attack.  On  the  con- 
trary, atropine  acts  as  a  paralyzant  on  the  autonomous  nerves  and  also  in- 
hibits the  activity  of  the  sympathetically  innervated  sweat-glands. 

The  fact  that  among  the  substances  mentioned  there  is  a  true  hormone, 
adrenalin,  leads  us  to  expect  that  this  direction  of  investigation  is  very  im- 
portant for  the  internal  secretions.  In  addition,  specific  affinities  for  the 
vegetative  nervous  system  are  shown  by  certain  ductless  glandular  extracts 
not  well  defined  chemically. 


26 


GENEILA.L    PART 


iiiUiiiiini  nt//  / 


•i     S; 


II 


DUCTLESS    GLANDS    AND    NERVOUS    SYSTEM  27 

Let  us  examine  more  closely  the  action  of  these  hormones  or  ductless 
glandular  extracts  in  this  direction. 

Of  adrenahn,  the  internal  secretion  of  the  chromaffin  tissue,  we  have  al- 
ready mentioned  that  it  is  of  great  significance  for  the  excitability  of  the 
myoneural  junctions.  As  in  a  genetic  relationship  the  chromaffin  tissue  be- 
longs to  the  sympathetic  system,  this  system  possesses  within  itself  a  regu- 
lator of  its  excitability  {Bayliss  and  Starling).  As  for  the  physiological 
significance  of  the  chromaffin  tissue,  it  must  furthermore  be  considered  that 
by  the  lasting  function  of  this  tissue  there  is  maintained  a  certain  dis- 
tribution of  blood.  The  sympathetic  innervation  of  the  different  vascular 
districts  is  of  different  richness;  for  example,  the  vessels  of  the  muscles  and 
skin  are  very  abundantly  suppKed,  while  the  vessels  of  the  lungs,  of  the 
coronary  arteries,  and  of  the  brain  possess  a  weak  sympathetic  supply. 
Priestley  and  /  have  pointed  out  that  the  venous  blood  emanating  from  the 
organs  with  a  rich  sympathetic  innervation  are  adrenalin-free  or  are  es- 
sentially poorer  in  adrenahn  than  the  arterial  blood  flowing  to  them.  The 
liver  is  supplied  with  blood  rich  in  adrenalin  only  by  the  hepatic  arteries, 
while  the  very  much  larger  amount  of  blood  that  flows  to  it  through  the  portal 
vein  is  adrenalin-free  or  at  least  poor  in  adrenahn,  as  this  blood  has  already 
passed  through  the  capihary  system  of  the  intestine.  Hence  in  a  quiet 
fasting  organism  there  occurs  a  definite  blood  distribution,  a  distribution 
that  may  be  regarded  as  purposeful.  Thus  the  resting  organs  (muscle, 
skin,  intestine,  etc.)  contain  very  little  blood,  while  those  organs  whose 
activity  is  necessary  for  the  maintenance  of  life  (heart,  central  nervous 
system,  lungs,  liver,  etc.)  are  relatively  rich  in  blood.  The  former  become 
supplied  with  more  abundant  blood,  through  the  regulatory  activity  of  the 
sympathetic  simultaneously  with  increased  cardiac  activity,  only  when  they 
are  functionally  more  in  demand. 

The  chromaffin  system  plays  an  important  role  in  the  regulation  of  the 
blood's  plasma  contents.  After  the  injection  of  large  amounts  of  adrenalin, 
Bertelli,  Schweeger  and  /  saw  an  appreciable  increase  in  the  count  of  the  red 
cells  of  the  circulating  blood.  As  this  hyperglobulia  survives  the  vaso-con- 
traction  for  a  long  time,  the  cause  of  this  is  to  be  sought  not  only  in  the  press- 
ing-out of  the  plasma,  but  also  in  an  alteration  of  the  permeability  of  the  ves- 
sel wall  on  account  of  which  the  return  flow  of  plasma  is  delayed  for  a  long 
time.  Now  it  is  known  that  in  individuals  who  are  brought  relatively  rapidly 
into  an  atmosphere  poor  in  oxygen  (mountains,  balloon  trips,  etc.)  the  num- 
ber of  red  blood  cells  increases  very  rapidly.  The  hyperglobulia  brings  about 
greater  respiratory  surface,  this  counterbalancing  the  slighter  partial  pressure 
of  the  oxygen.  To-day  it  is  generally  assumed  that  at  least  in  rapid  transi- 
tions it  is  not  the  result  of  the  increased  production  of  erythrocytes.  We 
believe  rather  that  it  is  due  chiefly  to  a  regulatory  exudation  of  plasma  into 
the  tissues,  and  that  in  this  regulation  is  involved  the  chromaffin  tissue. 


25  GENERAL    PART 

Finally,  our  investigations  have  shown  that  injection  of  adrenalin  pro- 
duces neutrophilic  hyperleucocytosis  and  induces  a  disappearance  of  the 
eosinophiles  from  the  circulating  blood.  Whether  this  is  due  directly  to 
excitation  of  the  sympathetic  nerves  or  indirectly  to  alteration  in  the  dis- 
tribution of  blood  is  hard  to  decide.  I  would  only  point  out  that  the  curves 
of  the  white  and  red  cells  are  not  parallel  throughout,  and  that  we  can  show 
that  drugs  such  as  pilocarpine  and  cholin  lead  always  in  the  first  stage  of 
their  action  to  an  appreciable  relative  and  absolute  increase  of  the  mono- 
nuclear cells,  eventually,  too,  to  a  changed  distribution  of  the  neutrophilic 
cells  in  the  vascular  tree.  These  accumulate  in  the  organs  less  well  in- 
nervated by  the  sympathetic,  such  as  the  lungs  and  the  liver,  while  there  are 
fewer  of  them  in  the  vessels  of  the  skin  and  muscles.  Hence  the  chromafltin 
tissue  seems  to  exercise  a  regulatory  influence  on  the  activity  of  the  blood- 
forming  apparatus,  chiefly  through  excitation  of  the  medullary  system 
[of  the  bones]. 

The  actions  of  thyroidin  on  the  nervous  system  are  far  more  manifold 
than  those  of  adrenalin.  We  must,  however,  refer  most  of  the  various  symp- 
toms of  hyperthyroidism  to  alterations  of  tonus  in  the  organs  supplied  by  the 
vegetative  nerves,  for  example,  the  tachycardia  to  excitations  of  the  sympa- 
thetic accelerator  nerve,  the  marked  fall  in  blood-pressure  to  diminution  of 
the  vascular  tonus  in  the  muscles,  skin,  and  intestinal  vessels,  the  irregularity 
of  the  breathing  to  a  heightening  of  the  vagal  tonus,  the  sweats  to  an  excita- 
tion of  the  nerves  of  the  sweat-glands,  etc.,  etc.  Probably  the  excitability 
throughout  the  entire  vegetative  nervous  system  is  increased,  although  an  elec- 
tive affinity  for  definite  sympathetic  or  autonomous  nerves  is  unmistakable. 

The  same  holds  true  for  extracts  of  the  hypophysis.  The  pituitrinum 
infundibulare,  obtained  from  the  posterior  lobe,  works  as  an  increaser  of  blood 
pressure  and  as  a  strong  diuretic;  it  also  acts  as  a  slower  of  the  pulse  through 
excitation  of  the  vagus,  and  as  an  increaser  of  excitability  of  the  autonomous 
nervus  pelvicus,  moreover  as  an  increaser  of  the  excitability  of  the  uterus, 
etc. ;  here  also  there  are  elective  affinities  for  certain  vegetative  organs  sup- 
plied by  the  sympathetic  or  autonomous  nerves. 

Pituitrinum  glandulare,  according  to  our  investigations,  changes  the  dis- 
tribution of  the  blood  in  the  opposed  sense.  It  reduces  blood-pressure  and 
lessens  the  volume  of  the  liver. 

Let  us  now  consider  the  alterations  of  the  excitability  on  the  tonus  of 
the  vegetative  organs  in  the  ductless  glandular  diseases. 

In  Basedow's  disease  there  is  an  abundance  of  symptoms  that  depend  on 
an  increased  tonus  of  both  the  autonomous  and  the  sympathetic  vegetative 
organs,  for  example,  the  tachycardia,  the  eye  symptoms,  the  sweats,  the  in- 
creased falls  of  blood-pressure,  etc.,  etc.  As  these  symptoms  are  found  in 
more  or  less  pronounced  manner  in  artificial  thyroidism,  the  conclusion  is 
justified  that  they  are  produced  also  in  Basedow's  disease  by  an  increased 


DUCTLESS    GLANDS    AND    NERVOUS    SYSTEM  29 

production  of  the  secretion  of  the  thyroid  gland.  Reversely,  in  typical 
myxedema  the  vegetative  functions  are  found  to  be  delayed,  slow;  the  excita- 
bihty  of  the  organs  supplied  by  the  sympathetic  and  autonomous  nerves  is 
reduced  (slower  pulse,  sluggishness  of  the  intestine,  etc.,  or  reduction  of  the 
glycosuric  action  of  adrenalin,  absent  or  deficient  hyperglobulia  after  the  in- 
jection of  adrenalin,  reduced  action  of  pilocarpine,  etc.). 

Then  again  the  parathyroid  bodies  influence  the  excitement  or  excitabihty 
of  the  vegetative  nerves.  In  the  acute  stage  of  tetany  are  found  hyper- 
globuha,  spasmodic  conditions  of  the  stomach  and  intestines,  the  bladder, 
ciliary  muscles,  the  heart,  etc.  The  different  actions  of  sympathicotropic  or 
automonotropic  agents,  such  as  adrenahn  and  pilocarpine,  are  essentially 
strengthened.  The  circumstance  that  in  tetany  the  manifestations  on  the 
part  of  the  vegetative  organs  are  essentially  different  from  those  of  Basedow's 
disease  shows  that  the  affinities  for  the  vegetative  organs  displayed  by  the 
hormone  of  the  parathyroids  and  the  hormone  of  the  thyroid  are  electively 
different;  and  also  the  point  of  attack  in  the  neuron  is  different,  as  in  the  one 
case  the  hyperirritability  [or  hyperexcitability,  Uberregbarkeit],  the  other 
the  hyperexcitement  [tjberregung],  is  more  prominent. 

In  Addison's  disease,  as  is  to  be  expected,  there  is  a  reduction  of  the 
excitabihty  and  a  slighter  tonus  of  the  organs  innervated  by  the  sympathetic, 
and  especiahy  prominent  are  the  reduction  of  the  blood-pressure  and  the 
lessened  action  of  adrenalin.  Here  the  picture  is  complicated  by  a  number  of 
symptoms  depending  on  a  strong  excitement  of  the  vegetative  organs,  symp- 
toms the  genesis  of  which  is  as  yet  doubtful. 

In  the  rest  of  the  ductless  glandular  affections  these  relations  are  still  less 
apparent.  I  shall  report  the  appropriate  investigations  and  observations  in 
the  respective  chapters,  and  here  shall  only  indicate  the  following:  In  hypo- 
physial dystrophy  and  in  eunuchoidism  the  excitabihty  of  some  of  the  vege- 
tative nerves  seems  to  be  somewhat  decreased.  Probably  there  exists  a 
certain  sluggishness  of  the  vegetative  functions,  which  however  does  not 
attain  the  degree  of  sluggishness  of  those  in  myxedema.  Diabetes  insipidus, 
which  not  rarely  is  associated  continuously  or  temporarily  with  diseases  of  the 
hypophysis,  seems  to  depend  on  an  irritation  of  the  posterior  lobe  of  the  hypo- 
physis or  on  a  specific  increase  of  the  function  of  the  kidneys.  In  acromegaly 
are  found,  not  rarely,  profuse  sweats,  even  when  no  other  manifestations 
of  complicating  hyperthyroidism  are  present.  In  some  cases  of  diabetes 
melhtus,  Lbwi  has  shown  an  increased  excitabihty  of  the  dilator  pupills, 
which  is  innervated  by  the  sympathetic;  we  found  in  a  definite  category  of 
cases  which  perhaps  are  similar  to  Lowi's  cases  a  strikingly  strong  glycosuric 
action  of  adrenahn;  in  such  cases,  in  which  also  the  neurogenous  factor  of  the 
glycosuria  markedly  predominates,  there  is  sometimes  found  an  increase  of 
blood-pressure  (hypertonic  diabetes). 

Also  the  glands  of  generation  seem  to  exercise  an  important  influence  on 


30  GENERAL    PART 

the  tonus  of  the  vegetative  organs.  This  is  expressed  in  the  female  sex 
especially,  in  the  form  of  the  known  wave-movement.  With  maturation  of 
the  follicles  (especially  of  the  fertilized  ovum  in  pregnancy)  there  occurs  an 
increased  vitality  of  the  whole  organism,  an  increase  of  the  vegetative  func- 
tions which  is  in  part  indirectly  due  to  the  higher  activity  of  the  whole  ductless 
glandular  system.  At  the  climacteric,  when  the  generative  glands  dis- 
continue their  function,  there  occurs  in  woman  lability  of  the  vegetative 
nervous  system,  especially  of  the  vasomotors,  a  sort  of  vasomotor  ataxia 
which  first  disappears  again  with  the  complete  loss  of  ovulation.  In  men 
too,  these  climacteric  disorders  occur,  although  they  are  rare. 

At  the  time  of  puberty  there  very  decidedly  sets  in  an  increase  of  vegeta- 
tive functions ;  it  is  attended  with  the  enormous  development  of  the  glands 
of  generation,  again  rather  stronger  in  woman  than  in  man;  it  often  takes 
place  in  an  incoordinated  manner,  giving  occasion  to  various  disturbances. 
In  specially  predisposed  female  individuals  the  revolutions  in  the  organism 
at  this  time  lead  to  an  exhaustion  which  seems  to  stand  in  relation  with  the 
development  of  chlorosis. 

In  the  other  ductless  glandular  diseases  the  behavior  of  the  vegetative 
nervous  sytem  is  still  less  clear.  In  premature  development  due  to  pineal, 
suprarenal  cortical,  or  sexual  glandular  tumors  this  pubertal  increase  of  the 
vegetative  functions  is  probably  anticipated.  As  to  the  influence  of  the 
thymus  glands  on  the  vegetative  nervous  system,  we  can  state  nothing  certain. 

This  condensed  survey  suffices  well  to  show  to  what  extent  the  activity  of 
the  vegetative  organs  and  the  excitability  of  the  vegetative  nervous  system  is 
influenced  by  the  ductless  glands.  This  direction  of  investigation  has  just 
been  determined  on.  As  to  its  further  development,  especially  when  physio- 
logical chemistry  has  established  still  more  hormones,  there  is  to  be  expected 
a  deepening  of  our  knowledge  as  to  the  symptomatology  of  the  ductless 
glandular  diseases.  From  the  observations  up  to  the  present,  however,  it 
may  be  stated,  although  with  insufficient  surety,  that  the  affinity  of  the 
hormones  for  the  vegetative  nerves  is  an  elective  affinity;  not  even  adrenalin 
itself  influences  the  entire  sympathetic  group,  for  it  leaves  the  sweat-glands 
unaffected.  The  other  ductless  glandular  extracts,  as  we  know,  always  show 
especial  elective  affinities  for  certain  organs,  whether  these  arc  supplied  by 
sympathetic  or  autonomous  nerves;  clinical  observations  furnish  still  more 
evidence  to  this  effect.  Hence  it  seems  to  me  improper  to  draw  too  extensive 
conclusions  from  the  pharmacological  tests  of  function.  Certainly  they  have 
furnished  us  with  very  valuable  inferences,  and  have  provided  a  deep  view 
into  the  functions  of  the  organ  innervated  by  the  vegetative  nervous  system. 
For  example,  LbwVs  reaction  is  practically  constant  on  the  dog  without  a 
pancreas.  Another  example  is  the  reduction  of  the  excitability  of  the  sym- 
pathetic nerves  after  extirpation  of  the  thyroid;  this  is  evidenced  not  only 
by  the  diminished  glycosuric  action  of  adrenalin,  but  also  by  the  remaining 


DUCTLESS    GLANDS    AND    NERVOUS    SYSTEM  3 1 

absent  of  a  marked  hyperglobulia.  This  also  occurs  in  typical  myxedema 
so  far  as  it  remains  uncomplicated  by  pathological  correlations,  for  ex- 
ample by  a  tetany.  I  believe,  however,  that  we  would  not  be  just  to  the 
complex  relationships  if  we  were  to  draw  from  the  result  of  such  functional 
tests  a  conclusion  as  to  the  condition  of  excitability  of  the  whole  sympathetic 
or  the  whole  autonomous  group.  In  this  respect  I  would  not  subscribe  to  the 
views  of  Eppmger  and  Hess  so  far  as  these  views  are  concerned  with  diseases 
of  the  ductless  glands.  These  are  based  chiefly  on  the  observations  that  in 
individuals  in  whom  adrenalin  works  diuretically,  the  action  of  pilocarpine 
remains  absent,  and  reversely  that  in  individuals  who  show  a  strong  pilocar- 
pine reaction,  adrenalin  does  not  produce  glycosuria.  The  absence  of  a 
glycosuric  action  of  adrenalin  does  not  show  that  the  entire  sympathetic 
group  is  hyposensitive.  Adrenalin  acts  as  a  raiser  of  blood-pressure,  accel- 
erates cardiac  action,  acts  as  a  diuretic,  produces  aneosinophilic  hyperleu- 
cocytosis,  etc.,  etc.  The  glycosuric  action  is  only  a  partial  manifestation  of  a 
very  manifold  action-complex.  Besides  this,  hyperglycemia  and  consider- 
able increase  of  the  respiratory  quotient  can  occur  without  glycosuria, 
if  diuresis  does  not  come  in  the  way;  and  besides,  perhaps  glycosuria  may 
remain  absent  in  cases  where  the  consumption  of  sugar  is  high.  We  saw,  for 
instance,  in  the  acute  stage  of  tetany,  absence  of  glycosuria  in  spite  of  enormous 
vascular  action.  In  other  cases  we  may  observe  marked  glycosuria,  while 
the  vascular  and  cardiac  action  remain  almost  entirely  absent.  In  bronchial 
asthma  I  never  saw  glycosuria  after  the  injection  of  adrenalin;  the  hyper- 
eosinophilia  which  was  often  present  was,  however,  diminished  markedly. 
Also  the  other  active  ductless  glandular  extracts,  as  for  example  thyroidin, 
show  such  a  dissociation  of  their  action. 

The  relations  are  rendered  still  more  complex  by  the  fact  that  individual 
organs  are  innervated  by  furthering  (fordern]  as  well  as  inhibitory  fibers  of 
the  same  group.  As  Elliot  has  shown,  adrenalin  in  minimal  doses  produces 
vascular  dilatation,  and  only  in  large  doses  vascular  contraction.  Pitui- 
trinum  infundibulare  increases  the  peristaltic  wave-movement  of  the  gravid 
rabbit  uterus.  The  same  extract  acts  for  the  most  part  inhibitory  on  the 
virginal  rabbit  uterus.  I  can  therefore  agree  with  Eppinger  and  Hess 
when  they  assume  a  relative  preponderance  of  the  autonomous  innervation 
in  an  insuflEiciency  of  the  chromaffin  tissue.  But  even  in  Addison's  disease 
(perhaps  through  failure  of  the  cortex,  perhaps  through  other  as  yet  obscure 
factors)  there  may  occur  acute,  highly  complex  conditions  of  excitement  in 
the  vegetative  nervous  system. 

In  many  later  works  there  is  found  the  tendency  to  distinguish  between 
vagotonic  and  sympathicotonic  conditions  in  ductless  glandular  diseases. 
For  instance,  Adler  supposes  after  the  failure  of  the  sexual  glands  a  sympa- 
theticotonic  condition,  on  account  of  the  fact  that  he  found  glycosuria  in  cer- 
tain castrated  individuals  after  the  injection  of  relatively  small  doses  of  adrena- 


32  GENERAL    PART 

lin.  while  pilocarpine  for  the  most  part  did  not  cause  sweating;  and  he  regards 
the  complicated  process  in  the  vegetative  nervous  system  in  dysmenorrhea 
as  vagotonic.     I  do  not  believe  that  these  things  allow  of  such  a  grouping. 

B.  Influence  of  the  Nervous  System  on  the  Function  of   the   Ductless 

Glandular  System 

I  now  come  to  the  consideration  of  those  relations  between  the  ductless 
glandular  system  and  the  nervous  system  which  are  characterized  by  the  fact 
that  the  ductless  glandular  system  is  itself  vegetative,  that  it  is  made  up  of 
organs  supplied  by  vegetative  nerves  that  possess  central  projection-lields. 
We  shall  have  investigated  in  what  measure  activity  of  the  ductless  glandular 
system  is  regulated  by  the  nervous  system.  Our  knowledge  as  to  this  kind 
of  relationship  is  as  yet  very  deficient.  We  may  scarcely  put  aside  the  sup- 
position that  in  this  respect  the  ductless  glands  behave  very  differently.  The 
impulses  emanating  from  the  central  nervous  system  are  very  important 
for  the  activity  of  the  chromaffin  tissue;  for  example,  perhaps  a  regulated 
activity  is  not  possible  even  for  a  short  time  if  the  central  innervation  is  want- 
ing. Centers  for  these  ductless  glands  he  on  the  floor  of  the  fourth  ventricle 
and  according  to  the  later  investigations  of  Aschner  also  in  the  subthalamic 
region.  Stimulation  of  these  centers  leads,  just  as  the  stimulation  of  the 
nervous  paths  proceeding  from  them  to  the  chromaffin  tissue,  to  the  dis- 
semination of  adrenalin.  Priestley  and  /  have  shown  that  after  interruption 
of  these  paths  by  transection  of  the  lowest  cervical  cord  the  amount  of  sugar 
in  the  blood  rapidly  decreases;  apparently,  therefore,  the  activity  of  the 
chromaffin  tissue  is  discontinued  if  its  connection  with  central  projection- 
fields  is  interrupted.  The  number  of  experiments  is  not  at  all  great,  as  the 
operative  attack  is  difficult.  It  seems  to  me,  however,  noteworthy  that 
indications  are  wanting  that  after  this  attack,  which  also  deprives  the  insular 
apparatus  of  its  central  innervation,  disturbances  in  the  insular  apparatus 
occur  during  the  short  time  that  the  animals  survive  the  attack.  I  would 
not  at  all  state  that  the  activity  of  the  insular  apparatus  is  not  regulated  by 
the  central  nervous  system;  it  seems,  however,  as  though  this  influence  were 
very  much  slighter  than  is  true  in  the  case  of  the  chromaffin  system ;  the  in- 
sular apparatus  seems  better  able  to  continue  its  activity  for  some  time  even 
after  interruption  of  its  connecting  paths.  That  the  production  of  the  assimi- 
latory  hormone  is  accessible  to  few  nerve  influences  seems  purposeful;  such 
ductless  glands  always  seem  to  work  with  a  certain  surplus;  while  the  giving 
off  of  the  dissimilatory  hormone  must  be  very  finely  graduated  in  order  to  do 
justice  to  the  rapidly  changing  demands;  this  is  only  possible,  however,  if 
the  central  nervous  system  governs  the  function  of  the  ductless  gland  furnish- 
ing them. 

That  the  activity  of  the  thyroid  gland  is  dependent  on  the  central  nervous 
svstem  mav  be  concluded  from  the  older  literature.     How  otherwise  can 


DUCTLESS    GLANDS    AND    HEMATOPOIETIC    APPARATUS  33 

we  explain  that  existence  of  an  acute  Basedow's  disease  with  the  rapidly 
developing  thyroid  swelling  that  comes  over  night?  Xewer  investigations 
of  Asher  and  Flack  make  it  very  probable  that  the  nerves  regulating  the  thy- 
roid glandular  activity  run  in  the  nervi  recurrentes.  These  investigations 
also  make  it  seem  possible  that  rapid  variations  in  the  function  of  the  thyroid 
gland  are  governed  by  nervous  influence. 

Practically  nothing  as  yet  is  known  in  this  connection  with  respect  to 
other  ductless  glands.  I  must  discuss  a  little  more  thoroughly  only  the 
sexual  glands.  The  sexual  glands  seem  to  assume  an  individual  position 
by  virtue  of  their  independence  of  the  central  nervous  system.  At  least 
the  results  of  transplantation  experiments  up  to  the  present  would  seem  to 
indicate  this.  With  the  thyroid  gland  only  autotransplantation  is  success- 
ful, that  is,  the  transplantation  of  the  thyroid  gland  to  another  place  in 
the  same  individual.  Homiotransplantation  (transplantation  to  another 
individual  of  the  same  kind)  fails.  But  up  to  the  present  it  has  not  been 
possible  to  maintain  autotransplants  capable  of  retaining  their  function, 
even  when  their  vessels  are  united  directly  wdth  the  vessels  of  the  part  by 
means  of  suture.  This  shows,  provided  of  course  that  the  efforts  of  the 
surgeons  are  not  crowned  with  success  at  some  time  in  the  future,  that  the 
function  of  the  thyroid  gland  is  not  possible  for  a  length  of  time  without 
connection  with  a  central  projection-field.  It  is  different  with  the  sexual 
glands.  Here  in  many  cases  not  only  autotransplantation  but  also  homio- 
transplantation succeeds.  Indeed  here  even  the  results  of  heterotransplanta- 
tion far  surpass  all  that  has  been  seen  on  the  transplantation  of  the  other 
ductless  glands.  This  separate  position  of  the  sexual  glands  was  really  to 
have  been  expected.  According  to  the  noteworthy  views  of  many  authors 
the  generative  glands  originate  from  the  primordial  cells,  which  through 
division  of  same  kind  of  preceding  cells,  the  ovum  and  the  spermatozoon, 
are  organisms  in  themselves  and  lead  an  independent  life.  That  the  sexual 
glands  are  also  accessible  to  influences  on  the  part  of  the  central  nervous 
system  and  have  central  projection-fields  in  no  way  contradicts  this  idea. 
According  to  Aschner  such  a  projection-field  lies  in  the  subthalmic  region. 
On  its  long-continued  excitation  degeneration  of  the  sexual  glands  occurs. 
Indeed  it  may  be  supposed  that  the  hypophysis  furnishes  trophic  influences 
to  the  sexual  glands  by  way  of  the  blood. 

If  we  summarize  the  little  we  know  concerning  this  important  subject 
we  find  that  the  ductless  glandular  system  shows  a  certain  degree  of  autonomy 
which,  however,  is  developed  in  very  di^fferent  ways  on  the  part  of  the  individual 
ductless  glands.  The  sexual  glands  are  provided  with  the  greatest  degree  of 
autonomy,  the  chromaffin  tissue  with  the  least. 

Influence  of  the  Ductless  Glands  on  the  Hematopoietic  Apparatus 

Before  I  speak  of  the  significance  of  the  influences  just  described  on  the 
pathogenesis  and  etiology  of  the  ductless  glandular  affections.  I  would  like 
3 


34  GENERAL    PART 

to  make  a  few  remarks  on  the  influence  that  the  ductless  glandular  system 
exercises  on  the  activity  and  development  of  the  liematopoielic  apparatus. 
I  should  like  to  emphasize  the  fact  that  the  thyroid  secretion  is  necessary 
for  a  normal  development  and  activity  of  the  hematopoietic  apparatus.  In 
myxedema  and  still  more  in  thyroid  glandular  insufiiciency  in  youthful  years 
do  disturbances  in  the  formation  of  blood  occur.  Especially  in  infantile 
myxedema  does  there  come  about  a  degree  of  anemia  which  is  often  not 
inconsiderable,  and  a  reduction  of  the  erythrocyte  count  and  the  amount  of 
hemoglobin;  the  involution  of  the  lymphatic  apparatus  is  insufficient;  in  the 
blood  picture  the  neutrophilic  leucocytes  retrogress,  and  the  mononuclear 
and  eosinophilic  predominate.  On  the  administration  of  thyroid  extract 
these  disturbances  disappear  wholly  or  at  least  in  great  part.  Similar,  but 
less  pronounced,  manifestations  occur  in  other  ductless  glandular  diseases 
due  to  absence  of  secretion,  as,  for  example,  hypophysial  dystrophy  and 
eunuchoidisin.  The  production  of  neutrophilic  granulocytes  hence  seems  to 
require  a  furthering  influence  on  the  part  of  the  thyroid  gland  and  chrom- 
afiin  tissue.  From  this  fact  are  elicited  relations  of  the  ductless  glands  to  the 
so-cafled  status  lymphaticus.  The  significance  of  a  hypoplasia  of  the 
chromaffin  system  for  this  condition  has  been  mentioned,  especially  by 
Wiedel,  Hedinger,  and  Eppinger  and  Hess. 

A  noteworthy  influence  on  the  hematopoietic  apparatus  is  exercised  by 
the  increase  of  function  of  the  thyroid  gland.  The  finding  of  KocJier,  that 
the  count  of  mononuclear  cells  in  the  blood  considerably  predominates,  is 
one  of  the  most  constant  features  of  Basedow's  disease.  In  addition  to  this 
relative  and  (to  a  great  extent)  absolute  increase  of  the  mononuclears  (and 
sometimes  of  theeosinophiles),  there  is  found,  just  as  frequently,  an  absolute 
diminution  of  the  neutrophilic  cells  in  the  circulating  blood.  Often  the 
relative  increase  of  the  former  is  only  the  sequel  of  the  absolute  diminution  of 
the  latter.  It  seems  to  me  that  in  this  connection  should  be  mentioned  the 
fact  that  BertelU  and  /  after  the  administration  of  thyroidin  to  dogs  found  an 
accumulation  of  neutrophilic  cells  in  the  blood  of  the  liver.  It  seems  there- 
fore that  thyroidin  influences  the  distribution  of  blood  in  the  vascular  tree. 
The  alterations  in  the  blood  picture  in  Basedow's  disease  are  therefore  not 
analogous  throughout  to  those  of  myxedema;  which  is  best  explained  by 
the  fact  that  on  administration  of  thyroidin  in  myxedema  the  blood  picture 
approaches  the  normal,  while  in  Basedow's  disease  it  diverges  from  the 
normal  (Falta,  Xeu'lnirg/i,  and  Xobel).  We  are  dealing  in  the  first  case  with 
symptoms  of  absence,  in  the  latter  case  with  irritative  manifestations. 

Same  as  has  already  been  described,  sympathicotropic  and  autonomo- 
tropic  substances  influence  the  blood  picture  and  the  distribution  of  the 
leucocytes  in  the  vascular  tree  in  a  definite  way,  we  can  comprehend  the 
fact  that  symptoms  of  irritation  in  ductless  glandular  affections  and  in  part 
also  the  symptoms  of  absence  are  the  result  of  an  altered  condition  of  ex- 
citability in  the  vegetative  nervous  system. 


PATHOGENESIS    AND    ETIOLOGY    OF    DUCTLESS    GLANDULAR   DISEASES       35 

With  this  agrees  the  fact  that  in  many  nervous  diseases  that  have  in- 
volved especially  or  partially  the  vegetative  nervous  system,  as  especially 
in  the  vagal  neurosis,  there  have  been  found  mononucleosis  and  eventually 
hypereosinophilia,  while  in  the  initial  stage  of  the  hypertonic  diathesis,  for 
example,  the  count  of  neutrophilic  cells  lies  at  the  upper  boundary  of  the 
normal  or  even  exceeds  this. 

On  long  continuance,  however,  there  are  found  in  many  ductless  glandular 
diseases  morphological  alterations  in  the  hematopoietic  apparatus.  The 
alterations  in  the  blood  pictures  that  are  observed  are  at  first  hand  very  hard 
to  interpret.  It  may  be  stated  that  in  acromegaly  there  is  very  frequently 
found  mononucleosis  and  eventually  slight  eosinophilia.  We  have  seen 
mononucleosis  in  chronic  tetany  (in  this  disease  under  the  influence  of  acute 
exacerbation  there  may  occur  rapid  reversals  of  the  blood  picture).  Mono- 
nucleosis (without  status  lymphaticus)  may  be  observed  even  in  severe 
diabetes.  I  agree  with  Borchardt,  who  has  likewise  studied  these  relations, 
that  in  general  in  most  of  the  ductless  glandular  diseases  there  is  observed 
a  tendency  to  mononucleosis  and  neutropenia,  and  in  many  a  slighter  or 
severer  grade  of  status  lymphaticus. 

Pathogenesis  and  Etiology  of  the  Ductless  Glandular  Diseases 

On  turning  our  attention  to  the  consideration  of  the  pathogenesis  and 
etiology  of  the  ductless  glandular  diseases,  we  find  that  the  idea  we  have  de- 
veloped as  to  the  influencing  of  the  function  of  these  glands  by  the  nervous 
system  is  not  without  significance.  However,  the  etiology  of  a  great  number 
of  ductless  glandular  diseases  is  to  be  sought  in  an  entirely  dift'erent  direction. 
Let  us  first  consider  the  diseases  due  to  absence  or  deficiency.  Here  we  meet 
with  congenital  aplasia  or  marked  hypoplasia,  as,  for  instance,  in  thyro- 
aplasia.  A  defective  development  [of  a  "rudiment"  or  '"Anlage"]  often 
seems  to  be  a  favorable  soil  for  a  later  infection.  Wiesel,  for  instance,  assumes 
that  a  tuberculosis  infection  very  frequently  becomes  established  in  the 
suprarenals  on  hypoplasias  of  the  chromaffin  tissue.  But  on  such  a  defective 
mapping  out,  an  insufficiency  may  become  manifest,  temporary,  or  perma- 
nent, even  without  the  addition  of  an  infectious  process,  if  larger  demands 
are  made  on  the  ductless  gland  in  question;  for  example,  glycosuria  may  occur 
on  marked  alimentary  overloading  with  carbohydrates  if  a  (often  heredi- 
tary) weak  mapping  out  of  the  insular  apparatus  is  present.  In  addition, 
we  should  mention  trauma.  This,  for  example,  may  aft'ect  the  testicles 
and  lead  to  eunuchoidism  or  late  eunuchoidism;  in  operation  on  goiter  too 
much  of  the  functionating  thyroid  glandular  tissue  may  be  extirpated,  or  the 
parathyroid  glands  may  be  injured.  A  very  great  role  in  the  pathogenesis 
of  the  disease  due  to  absence  is  played  by  infection.  Tuberculous,  luetic,  or 
other  bacteriological  processes,  most  as  yet  not  investigated,  may  temporarily 
damage  the  ductless  glands  or  lead  to  permanent  destruction  or  sclerosis. 


36  GENERAL    PART 

These  infectious  processes  may  spread  to  the  ductless  gland  from  the  neigh- 
borhood, they  may  affect  the  acini  of  the  pancreas  through  the  ducts  and 
involve  the  insular  apparatus  by  contiguity;  in  most  cases,  however,  the 
infection  follows  by  the  hematogenous  route.  In  many  cases  in  which  the 
infectious  process  involves  many  ductless  glands  at  a  time  and  causes  de- 
struction (multiple  ductless  glandular  sclerosis),  a  congenital  or  acquired 
predisposition  of  the  ductless  glandular  system  is  perhaps  present.  Also 
chronic  intoxications,  as  alcoholism,  poisoning  by  the  toxin  of  goiter,  etc., 
may  damage  single  or  several  ductless  glands.  Furthermore,  tumors  that 
proceed  from  parts  in  the  neighborhood  or  from  the  ductless  gland  itself  may 
destroy  the  functionating  tissue.  Again,  in  many  ductless  glands,  purely 
functional  disturbances  on  a  nervous  basis  are  possible,  analogous  to  those 
hyposecretions  that  occur  in  glands  with  external  secretion.  The  possi- 
bility of  a  functional  Addison's  disease  was  long  ago  discussed  by  v.  Neusser. 
A  like  supposition  seems  to  me  debatable  for  the  chromaffin  tissue  or  for 
the  pancreatic  insular  apparatus.  Xor  would  trophic  degenerations  of  the 
ductless  glands  be  impossible. 

A  greater  importance  should  be  ascribed  to  nervous  influences  in  the 
pathogenesis  of  the  diseases  of  hyperfunction.  The  pathologico-anatomical 
correlate  of  hyperfunction  is  hyperplasia,  or  in  ductless  glands  of  definite 
morphological  structure,  of  adenoma  formation.  The  latter  is  found  in 
the  disease  of  hyperfunction  of  the  glandular  hypophysis,  of  the  thyroid 
gland,  and  the  suprarenal  cortex;  while  in  the  sexual  glands  sarcomatoid 
tumors  are  more  often  found.  Hyperplasia  of  the  chromaffin  tissue  is  found 
in  the  hypertonic  diathesis.  Even  where,  however,  the  adenoma  formation  is 
most  common,  indeed  constant,  can  a  nervous  cause  of  the  hyperfunction  not 
always  be  precluded.  In  peracute  Basedow's  disease,  the  entire  symptom- 
complex  and  the  swelling  of  the  thyroid  gland  can  develop  in  a  few  hours;  here 
we  cannot  well  blame  the  adenoma  formation,  as  it  is  very  much  more  likely 
that  in  such  cases  the  adenoma  formation  sets  in  at  some  later  stage  of 
the  disease.  Such  cases  and  the  fact  that  many  symptoms  of  Basedow's 
disease,  for  instance  the  marked  exophthalmos,  can  hardly  be  produced  by 
hyperthyroidization  have  led  certain  authors  back  to  the  conception  of  the 
older  French  authors,  according  to  which  Basedow's  disease  was  regarded 
as  a  vegetative  neurosis  and  in  which  many  of  the  symptoms  of  the  Basedow's 
were  considered  as  coordinated  with  the  hyperthyroidism.  According  to 
this  we  might  distinguish  Basedow's  disease  as  a  hyperthyrosis  from  the 
symptom-complex  of  hyperthyroidism.  Whether  such  views  are  to  be  ap- 
plied to  the  adenomata  of  the  hypophysis  and  suprarenal  cortex  can  hardly 
be  decided  at  the  present  time.  As  far  as  severe  diabetes  is  concerned,  we 
can  hardly  get  away  from  the  assumption  of  a  hyperfunction,  whether  it  be 
secondary  or  primary.  In  Chapter  XIII  the  opinion  will  be  advocated  that 
the  entire  apparatus  regulating  sugar  metabolism  (central  projection-fields, 


CENTRAL    NERVOUS    SYSTEM    AND    DUCTLESS    GLANDS  37 

pancreas,  and  chromaffin  tissue  as  organs  affected  by  these  fields)  is  diseased, 
in  the  course  of  which  disease  process  diminution  of  function  in  one  part  and 
excess  of  function  in  another  come  to  exist  in  juxtaposition. 

Nor  can  we  explain  the  cause  of  the  hyperfunction  better  if  we  regard 
as  its  seat  the  central  projection-fields.  The  problem  is  only  shifted, 
although  we  cannot  deny  that  in  this  manner  the  solution  of  the  symptom- 
complex  is  made  easier,  or  indeed  first  made  possible. 

Relation  between  Diseases  of  the  Central  Nervous  System  and  the  Duct- 
less Glandular  System 

The  knowledge  that  the  ductless  glands  as  vegetative  organs  indeed  show 
a  certain  autonomy,  but  in  part,  as  far  as  their  function  is  concerned,  stand 
under  control  of  the  central  nervous  system,  together  with  the  supposition 
that  we  have  to  reckon  with  the  possibility  of  a  purely  functional  increase 
or  decrease  of  their  secretion,  requires  of  us  that  we  now  investigate  whether 
in  the  diseases  of  the  central  nervous  system  alterations  of  the  ductless  glands 
are  demonstrable.  The  investigations  should  first  of  all  be  important 
for  neuroses  of  the  vegetative  nervous  system,  but  must  also  reach  to  the 
psychoses  and  the  other  diseases  of  the  central  nervous  system.  So  far  as 
the  psychoses  are  concerned  there  have  been  pointed  out  very  recently  ap- 
preciable variations  in  the  condition  of  excitement  and  the  tonus  of  the 
vegetative  organs.  I  refer,  among  other  investigations,  to  the  investigations 
of  Pbtzl^  Eppinger,  and  Hess,  who  have  found  in  melancholia  a  reduction 
in  the  excitability  of  the  vegetative  nervous  system,  and  in  mania,  especially 
during  the  first  attack,  appreciable  heightening  of  the  excitability  of  the 
vegetative  nervous  system.  Also  in  other  diseases  of  the  central  nervous 
system,  for  example  in  tabes,  symptoms  on  the  part  of  the  vegetative  nervous 
system  become  conspicuous  in  the  disease  picture. 

This  investigation  seems  to  have  so  much  the  more  force  because  later  ob- 
servations always  confirm  the  view  that  in  diseases  of  the  nervous  system  and 
in  the  psychoses^  the  metabolism  is  often  altered  in  a  profound  way.  I  would 
here  quote  some  examples.  Rosenfeld  first  established  that  a  considerable 
nitrogen  retention  occurs  in  catatonics.  Siege  found  enormous  variation  in 
the  nitrogen  elimination  in  the  circular  psychoses.  Especially  intensive 
studies  on  metabolism  have  been  made  by  Kaufmann  from  Antonys  clinic. 
Especially  mentionable  are,  for  example,  the  enormous  variations  in  body 
weight  in  psychoses:  for  instance,  Kaufmann  found  rapid  fall  of  the  body 
weight  in  spite  of  copious  forced  feeding.  According  to  Kaufmann,  such  rapid 
variations  are  to  be  referred  chiefly  to  disturbances  in  the  amount  of  water  in 
the  organism  in  the  wake  of  nervous  influences.  In  hysteria,  Kaufmann  found 
considerable  variations  in  the  amount  of  urine  and  in  body  weight,  together 
with  the  fact  that  the  pyschical  disturbances  may  recede  while  the  vegetative 

'  For  remarks  as  to  the  results  of  the  Abderhalden  reaction  in  mental  diseases  see  foot-note, 
p.  49. — Editor. 


38  GENERAL    PART 

disturbances  are  still  present.  Also  in  progressive  paralysis,  in  tabes,  and  in 
a  series  of  other  brain  diseases  are  alterations  of  the  metabolism  observed — 
Paghini  found  in  many  brain  diseases  increase  of  the  elimination  of  endogenous 
uric  acid  and  of  the  xanthin  bases.  Lowe  found  increase  in  the  elimination  of 
phosphorus  after  epileptic  attacks  and  in  definite  phases  of  the  paralysis  and 
in  delirium  tremens.  The  thought  has  also  been  expressed  that  the  appreci- 
able indicanuria  accompanying  brain  diseases  is  sometimes  of  nervous  origin. 
There  are  also  observed  in  cerebral  and  mental  diseases  considerable  varia- 
tions in  the  salt  metabolism.  As  is  known,  there  is  frequently  found  in 
neurasthenia  considerable  increase  in  the  elimination  of  calcium.  The 
brittleness  of  the  bones  that  is  so  often  seen  in  tabes  indicates  a  considerable 
loss  of  calcium  and  phosphorus.  Disturbances  in  the  carbohydrate  met- 
abolism (especially  appreciable  lowering  of  the  assimilation  boundary)  are 
frequent  phenomena  in  cerebral  and  mental  disturbances.  Disturbances 
of  the  regulation  of  the  heart  are  not  at  all  a  rare  symptom.  In  progressive 
paralysis  Kaufmann  often  found  hyperthermia,  and  in  the  akinetic  diseases  as 
well  as  after  epileptic  attacks  reduction  of  temperature.  These  few  examples 
might  suffice.  It  can  well  be  conceived  that  these  alterations  in  metabolism 
come  about  through  a  functional  influencing  of  the  ductless  glandular  system. 

Special  attention  has  been  devoted  in  this  respect  to  the  behavior  of  the 
ductless  glands  in  the  neuroses  of  the  vegetative  nervous  system.  Egger 
saw  in  the  vasomotor  psychoneuroses  increases  of  temperature  that  lasted  for 
months  and  years.  In  visceral  neuroses,  Pollitzer  saw  positive  alimentary 
galactosuria,  while  alimentary  glycosuria  was  negative.  This  reminds  one  of 
the  alimentary  levulosuria  described  by  the  author  in  some  cases  of  Basedow's 
disease,  or  in  the  disturbances  in  the  qualitative  decomposition  of  protein  in 
tetany.  Curschmann  saw  a  case  of  bronchial  asthma  with  intermittent 
exophthalmus,  tremor,  and  tachycardia.  In  the  vagal  neurosis  I  regularly 
found  appreciable  mononucleosis  of  the  blood,  and  Eppingcr  and  Hess  ob- 
served also  hypereosinophilia.  In  the  vasomotor  neurosis  Roth  found  in  ad- 
dition to  marked  lymphocytosis  and  labihty  of  the  pulse,  also  labihty  of  the 
temperature.  Why  rare  cases  of  pentosuria  and  isolated  levulosuria  are  almost 
always  associated  with  vasomotor  neurosis  is  as  yet  unexplained.  A  short 
time  ago  I  saw  a  case  of  pentosuria  with  pronounced  Herz's  vasomotor  ataxia. 

In  Raynaud's  disease  is  often  seen  slight  rise  in  temperature,  distinct 
trophic  and  secretory  disturbances,  and  in  the  attack  often  marked  rise  in 
blood-pressure;  sometimes  there  is  polyuria  and  in  rare  cases  glycosuria. 

Partially  related  to  the  vasomotor  neurosis  is  perhaps  that  condition  which 
affects  the  group  of  diabetics  in  which  the  neurogenous  factor  especially  pre- 
dominates in  the  glycosuria.  Here  we  usually  find  marked  vasomotor  ex- 
citabihty,  and  under  circumstances  increase  of  the  blood-pressure  without 
nephritis  (hypertonic  diabetes,  see  Chapter  XIII). 

Among  the  many  symptoms  of  the  vasomotor  neuroses  are  found,  accord- 


CENTRAL    NERVOUS    SYSTEM   AND    DUCTLESS    GLANDS  39 

ing  to  this,  those  which  point  to  an  alteration  in  the  metaboHsm  and  in 
general  to  a  functional  influencing  of  the  ductless  glandular  system.  It 
seems  to  me  that  there  is  wanting  in  this  case  any  secure  foundation  for 
bringing  a  primary  alteration  of  the  ductless  glandular  system  into  an  etio- 
logical relationship. 

Of  the  vasomotor  neuroses,  scleroderma  seems  to  merit  a  more  exact  con- 
sideration. In  this  affection  there  are  a  series  of  findings  that  point  to  a 
marked  involvement  of  the  ductless  glandular  system,  v.  Strumpell  has 
pointed  out  a  certain  opposition  in  the  symptom  picture  of  scleroderma  and 
acromegaly.  In  the  latter  the  bones  and  skin  are  hyperplastic,  while  in  the 
former  there  are  processes  of  shrinkage  in  both  organs.  The  opinion  that 
the  basis  of  scleroderma  is  a  functional  disturbance  of  the  hypophysis  finds, 
according  to  Roux,  corroboration  through  the  fact  that  in  this  case  apparent 
sclerotic  processes  are  found  in  the  hypophysis.  Until  the  present,  however, 
this  case  has  remained  isolated;  the  opinion  is  often  expressed  that  sclero- 
derma depends  on  an  alteration  of  function  of  the  thyroid  gland.  After 
V.  Leiibe  first  pointed  out  the  coexistence  of  scleroderma  with  Basedow's 
disease,  numerous  pertinent  cases  were  found  in  the  literature,  which  have 
been  compiled  by  Saltier.  Cassirer  mentions,  however,  that  in  these  cases 
the  diagnosis  Basedow's  disease  is  to  be  accepted  with  caution,  as  im- 
portant symptoms  of  Basedow's  disease,  such  as  pigment  displacements, 
changes  in  the  thyroid  gland,  irritability  of  the  heart,  also  belong  to  sclero- 
derma in  itself.  Even  the  exophthalmus  may  be  stimulated  by  the  sclero- 
dermic mask.  Cassirer  himself  calls  attention  to  the  fact  that  these  symp- 
toms similar  to  Basedow's  do  not  always  follow  in  their  intensity  the  course 
of  sclerodermic  process.  The  occasional  appearance  of  myxedemic  symptoms 
(Grasset,  Osier,  Dehu,  et  al.)  and  the  not  rare  finding  of  sclerotic  changes  in  the 
thyroid  glands  of  those  sick  with  scleroderma  have  permitted  Jeanselme, 
Singer,  Hectoen,  v.  Notthaft,  Leredde  and  Thomas,  and  others  to  regard  the 
cause  of  the  scleroderma  as  an  insufficiency  of  the  thyroid  gland,  the  more 
probably  for  the  reason  that  in  many  cases  good  results  are  obtained  by 
thyroid  medication.  The  common  occurrence  of  pigmentations  in  sclero- 
derma seems  to  indicate  the  associated  involvement  of  the  chromaffin  tissue. 
The  pigmentations  may  simulate  those  of  Addison's  disease.  In  not  rare 
cases  there  are  also  observed  typical  smoke-gray  discolorations  of  the  mucous 
membrane  of  the  mouth.  In  a  large  number  of  cases  the  combination  of 
scleroderma  with  Addison's  disease  has  also  been  assumed,  although  there  are 
numerous  observations  {Lichtwitz,  Kren,  and  others)  of  scleroderma  with 
typical  Addisonoid  pigmentations  of  the  skin  and  mucous  membranes  that 
showed  no  alterations  in  the  suprarenal  glands  at  autopsy.  Finally  the 
combination  of  scleroderma  with  tetany  has  been  described  in  a  case  of 
Dupre  and  Guillain's.  In  this  case  it  seems  as  though  a  pronounced  Addison's 
disease  were  also  present.     As  the  supposition  of  change  in  one  ductless 


40  GENERAL    PART 

gland  is  not  satisfactory,  there  has  been  upheld  by  several  recent  authors  a 
pluriglandular  pathogenesis  of  scleroderma  (Dupre  and  Kahn,  Rasch,  and 
others).  With  regard  to  this,  it  is  conceivable  that  sclerotic  processes  in 
certain  ductless  glands  in  scleroderma  do  not  mean  very  much.  The  sclero- 
derma often  spreads  to  the  deeper-lying  tissue  and  may  also  extend  to  the 
bones  and  muscles;  it  is  therefore  not  wonderful  if  now  and  then  the  proc- 
ess should  involve  individual  ductless  glands.  Moreover,  there  are  found 
in  the  majority  of  cases  of  scleroderma  a  great  number  of  manifold  symp- 
toms on  the  part  of  the  vegetative  nervous  system,  conditions  of  excitement 
of  manifold  nature,  such  as  vasomotor  disturbances,  tachycardia,  shivering, 
faintings,  rush  of  blood  to  the  head,  feeling  of  anxiety;  as  Klinger  observed, 
such  conditions  may  occur  in  attacks.  Hess  and  Kdnigstein  saw  in  one  case 
of  diffuse  scleroderma,  during  such  attacks,  an  especial  sensitiveness  against 
adrenalin  and  marked  excitement  of  the  heart-action,  associated  with  mani- 
festations of  acroparesthesia  and  with  subsequent  outbreaks  of  sweat.  In 
addition  to  this  are  found  in  the  majority  of  cases  a  series  of  trophic  distur- 
bances, such  as  transitory  edema,  erythema,  urticaria,  etc.  These  make 
the  diagnosis  of  a  coexistent  Basedow's  disease  very  much  more  difficult. 
On  the  other  hand,  I  do  not  doubt  that  in  many  of  the  cases  there  was 
actually  an  increase  of  function  of  the  thyroid  gland,  and  that  it  was  not 
at  all  impossible  that  the  pigmentations  had  their  basis  in  a  disturbance  of 
function  of  the  chromaffin  tissue.  Nor  do  I  doubt  that  in  certain  cases 
slight  symptoms  of  thyroid  insufficiency  may  occur.  When  I  acknowledge, 
therefore,  the  possibility  of  pluriglandular  symptoms  in  scleroderma,  I  would 
regard  them  as  only  secondary,  in  part  due  to  the  sclerodermic  process  ex- 
tending over  the  ductless  glands,  and  still  more  due  to  functional  influenc- 
ing of  the  ductless  glandular  system.  There  are  in  addition  cases  of  sclero- 
derma in  which  the  manifestations  on  the  part  of  the  vegetative  nervous 
system  are  much  less  prominent. 

I  agree  fully  with  Cassirer  in  the  supposition  that  in  scleroderma  the  dis- 
ease process  is  not  primary  in  the  ductless  glandular  system. 

There  has  also  been  an  attempt  to  bring  another  group  of  diseases,  the 
trophoneuroses,  into  relation  with  the  ductless  glandular  system,  diseases 
such  as  acute  circumscribed  edema  and  symmetrical  lipomata.  In  both 
are  regularly  found  neurosis  symptoms  on  the  part  of  the  vegetative  nervous 
system.  Here  also  is  found  the  possibility  of  functional  disturbances  on 
the  part  of  the  individual  glands,  although  the  symptoms  are  here  less  dis- 
tinctly prominent.  This  same  thing  seems  to  me  to  hold  good  for  adipositas 
dolorosa.  This  condition  will  be  considered  in  detail  in  Chapter  XI\';  here 
I  wish  to  dispense  with  the  supposition  of  ductless  glandular  etiology.  The 
same  is  true  for  xanthelasma,  the  pathology  of  which  Chvostek  has  made 
the  subject  of  a  penetrating  study.  Chvostek  in  consideration  of  the  occur- 
rence [of  xanthelasma]  in  gradations  [schubweise],  the  kind  of  distribution, 


CENTRAL    NERVOUS    SYSTEM    AXD    DUCTLESS    GLANDS  41 

and  especially  the  often  rigid  symmetry,  comes  to  the  conclusion  that  nervous 
influences  are  the  basis.  The  individual  with  xanthelasma  shows  a  series 
of  SATnptoms  on  the  part  of  the  nervous  system  and  especially  on  the  part 
of  the  vegetative  nerves.  Here  also  the  changes  in  the  ductless  glands 
seem  to  me  to  be  only  of  a  secondary  nature. 

Xot  only  in  trophoneuroses,  but  also  in  other  diseases  of  the  central 
nervous  system,  do  we  find  the  most  manifold  symptoms  that  point  to  dis- 
turbances in  the  function  of  the  vegetative  nervous  system.  It  seems  to 
me  that  the  study  of  these  conditions  has  been  handled  rather  half-heartedly 
by  neurologists.  Myasthenia,  paralysis  agitans.  and  myotonia  have  been 
brought  into  etiological  connection  with  the  parathyroid  glands.  As  we 
shall  see,  however,  in  Chapter  IV,  I  regard  the  hypothesis  of  a  primary  aft"ec- 
tion  of  the  parathyroid  glands  in  these  diseases  as  insufficiently  supported. 
Myasthenia,  because  like  scleroderma  it  is  sometimes  associated  with  slight 
symptoms  of  Basedow's  disease  or  tetany  (Tobias),  has  been  regarded  as  a 
polyglandular  disease  (Markelof),  certainly  not  with  more  correctness  than 
has  been  scleroderma.  Finally,  I  wish  to  make  some  remarks  in  this  connec- 
tion with  regard  to  multiple  sclerosis,  tabes,  and  progressive  paralysis.  In 
multiple  sclerosis,  often  symptoms  on  the  part  of  the  vegetative  nervous 
system  become  distinctly  prominent.  There  often  exist  tachycardia  and 
great  lability  of  the  pulse,  mostly  pronounced  dermographism,  furthermore, 
sweats,  inclination  to  h^-perthermia,  manifestations  on  the  part  of  the  gastro- 
intestinal canal,  poljoiria,  bladder  disturbances,  etc.  In  a  series  of  cases 
that  we  investigated  we  found  a  great  sensitiveness  against  adrenalin  and 
pilocarpine,  often  appreciable  alimentary  glycosuria,  strong  diuretic  action 
of  pituitrinum  infundibulare,  low  degree  of  tolerance  against  thyroidin,  etc. 
In  some  cases  even  Chvostek's  phenomenon  was  observed.  It  is  further  known 
that  in  multiple  scleroses  the  activity  of  the  generative  glands  mostly  dis- 
appears early.  I  think  that  most  will  agree  with  me  that  if  we  speak  of 
pluriglandular  disturbances  in  this  disease,  we  shall  have  to  assume  a  func- 
tional and  trophic  influencing  of  the  ductless  glands.  The  relations  in  tabes 
and  progressive  paralysis  seem  to  me  to  be  very  similar.  Kraepelin  has 
grouped  paralysis  with  the  diseases  of  metabolism,  to  which  group  Raymond 
has  ascribed  tabes.  This  seems  to  me  to  be  overdrawn.  In  the  same  manner 
we  could  regard  the  infectious  diseases  as  metabolic  diseases.  Indeed  it  is  true 
that  in  tabes  and  paralysis  the  alterations  of  metabolism  are  so  prominent  that 
at  times  they  almost  dominate  the  clinical  picture.  I  refer  to  the  losses  of 
weight,  to  the  marked  cachexia  of  tabetics,  to  the  decalcification  of  the  bones, 
which  gives  rise  to  the  spontaneous  fractures,  to  the  positive  alimentary 
glycosuria  that  is  so  marked  in  this  condition;  also  to  the  irritative  symp- 
toms on  the  part  of  the  nervous  system  that  are  so  fulminant,  the  tabetic 
gastric  crises,  the  vesico-intestinal  crises,  the  enormous  h3^ersecretion  of 
gastric  juice,  moreover  the  vasomotor  disturbances,   tachycardia,   sweats, 


42  GENERAL    PART 

dermographism,  and  the  trophic  disturbances,  abnormal  pigmentations, 
mal  perforant  du  pied.  etc.  If  here  I  look  around  for  S}Tnptoms  on  the  part 
of  the  ductless  glands.  I  find  almost  only  the  degenerative  changes  in  the 
sexual  glands  that  have  been  demonstrated  by  Marchand  and  others;  these 
may  be  conditioned  by  the  syphilis,  but  it  might  also  be  conceived  that  they 
exist  on  a  trophic  degenerative  basis.  I  could  regard  any  of  the  other 
s>Tnptoms  as  ductless  glandular,  only  in  the  sense  that  they  might  be  second- 
ary. R.  Stern  regards  as  the  basis  of  the  fact  that  only  a  percentage  of  persons 
infected  with  lues  become  affected  with  metasyphilis  the  vulnerability 
of  the  ductless  glandular  system  in  the  mapping  out  [Anlage]  of  such  persons. 
According  to  this  view,  the  aft'ection  of  these  glands  furnishes  the  impulse  for 
the  development  of  the  tabes  or  the  paralysis.  Even  though  in  my  dis- 
sertations I  arrive  at  a  standpoint  that  is  almost  the  opposite  of  Stern  s.  I 
would  nevertheless  recognize  the  ingenious  character  of  Stern's  work. 

I  would  here  summarize  briefly  the  facts  arrived  at  from  the  above  exposi- 
tion. Even  though  we  may  be  inclined  to  refer  to  functional  alterations  of 
the  ductless  glandular  system  changes  in  metabolism  in  the  course  of  neuro- 
ses of  the  vegetative  nervous  system  or  in  the  course  of  nervous  diseases  in 
which  manifestations  on  the  part  of  the  vegetative  nervous  system  become 
prominent,  we  are  not  on  this  account  justified  in  regarding  these  diseases 
as  true  ductless  glandular  aft'ections.  At  all  events  it  must  be  acknowledged 
that  it  is  not  yet  possible  to  draw  a  clear  line  of  demarcation  between  certain 
ductless  glandular  affections  and  the  vegetative  neuroses;  the  neurosis  theory 
of  Basedow's  disease  has  not  as  yet  been  fully  rejected,  nor  is  the  supposition 
that  in  the  pathogenesis  of  diabetes  mellitus  there  is  the  admixture  of  a 
marked  component  of  neurosis.  But  a  sufficiently  firm  foundation  has  been 
built  by  experimental  pathology,  in  the  majority  of  ductless  glandular 
aft'ections.  to  justify  a  sharp  demarcation  from  the  vegetative  neuroses,  at 
least  nosologically. 

Pluriglandular  Disturbances 

Proceeding  from  this  standpoint,  we  now  go  on  with  a  consideration  of 
the  question  of  the  pluriglandular  disturbances.  Of  late  this  question  has 
been  especially  discussed  in  France.  Claude  and  Gougerot.  on  the  basis  of 
clinical  observations  and  certain  pathologico-anatomical  findings,  first 
conceived  the  idea  of  an  insufiisance  pluriglandulaire.  Proceeding  from  the 
observation  that  under  circumstances  certain  ductless  glands  may  become 
diseased  simultaneously,  they  attempted  to  furnish  the  demonstration  that 
in  the  most  diverse  ductless  glandular  diseases  symptoms  are  found  almost 
regularly  that  point  to  the  aft'ection  of  another  ductless  gland.  The  authors 
have  found  many  disciples.  The  direction  of  this  is  characterized  by  the 
classification  of  Laignel-Lavastine.  Laignel-Lavastine  distinguishes  "syn- 
dromes pluriglandulaires  a  predominance  thyreoidienne.   a    predominance 


PLURIGLANDULAR    DISTURBANCES  43 

hypophysaire,  a  predominance  genitale  et  sans  predominance  marquee." 
Claude  and  Gougerot  have  further  developed  their  teaching  in  that  they  point 
out  that  also  conditions  of  hyperfunction  of  several  ductless  glands  may 
exist  simultaneously,  and  that  not  rarely  conditions  of  hyperfunction  of  one 
ductless  gland  are  combined  in  the  clinical  picture  with  manifestations  of 
absence  or  deficiency  of  the  function  of  another.  They  distinguish,  of  duct- 
less glandular  diseases,  seven  categories: 

1.  Syndromes  uniglandulaires  avec  lesion  pluriglandulaire ;  example, 
classical  myxedema. 

2.  Syndromes  pauciglandulaires;  that  is,  predominance  of  the  disease  in 
one  ductless  gland,  but  distinct  alteration  in  the  others. 

3.  Syndromes  d'insufhsance  pluriglandulaire  sans  predominances. 

4.  Syndromes  d'hyperfonction  pluriglandulaire;  example,  acromegaly, 
hyperfunction  or  dysfunction  of  the  hypophysis  with  hyperfunction 
of  the  thyroid  gland,  suprarenal  glands,  etc. 

5.  Syndromes  pluriglandulaires  de  balancement;  that  is,  a  hyperfunction 
that  developed  compensatorily  as  the  result  of  a  primary  falling  away 
of  the  function;  for  example,  Basedow's  disease  that  follows  a 
"hypoovarie." 

6.  Syndromes  pluriglandulaires  disharmoniques;  example,  Basedow's 
disease  combined  with  myxedema  and  "hypoovarie." 

7.  Cas  d'attente  a  syndromes  frustes. 

Gougerot  goes  still  further,  including  the  glands  with  external  secretion 
in  the  pluriglandular  syndrome;  for  instance,  he  describes:  syndrome 
Mikulicz,  lacrymo-parotidien  avec  symptomes  d'hypoovarie  evidente,  hy- 
pothyreoidie  et  hypoepinephrie  probable.  The  disciples  of  Claude  and 
Gougerot  have  also  included  the  trophoneuroses.  Thus  Siccard  and  Rousay, 
later  together  with  Berkowitsch,  explain  a  case  of  Dercum's  disease  as  in- 
sufhsance  ovarothyreoidienne.  From  these  views  Renon  and  Delille  have 
drawn  far-reaching  therapeutic  consequences,  in  that  they  propose  an 
"opotherapie  associee"  in  those  conditions  in  which  a  trial  with  simple 
opotherapy  fails.  Thus  the  authors  found  that  in  one  case  of  Dercum's 
disease  ovarian  substances,  and  later  thyroidin,  remained  inactive,  while 
on  the  contrary  the  combination  of  these  two  remedies  was  effective.  A  case 
of  myasthenie  bulbospinale  was  improved  by  the  combined  administration 
of  ovarian  and  hypophysial  substances,  a  scleroderma  by  thyroidin  and 
ovarian  substances,  a  Basedow's  disease  disappeared  on  the  administration 
of  hypophysial  and  ovarian  substances,  a  case  of  acromegaly  was  essentially 
improved  through  ovarian  substances  and  thyroidin,  etc.  R.  Dupuy  used 
polyopotherapy  for  the  development  of  individuals  who  had  remained  be- 
hind or  were  at  a  standstill,  and  saw  a  striking  improvement  after  one-half 
to  one  year's  treatment.  The  admixture  of  all  nosological  unities  goes  so 
far  that  Grasset  says:  The  insufhciency  of  a  ductless  gland  always  becomes 


44  GENERAL    PART 

more  and  more  a  rarity  or  a  "creation  artiticielle,"  the  group  of  insuffisance 
pluriglandulaires  crowds  the  others  more  and  more  and  perhaps  in  time  will 
quite  replace  them.  With  all  this,  who  does  not  feel  foundations  wavering 
under  him? 

I  must  not  leave  unmentioned  the  fact  that  voices,  even  in  France, 
have  been  raised  against  these  extreme  overdrawings.  Roiissy  maintains  a 
very  reserved  attitude.  He  believes  that  they  are  an  ingenious  hypothesis, 
but  [regards]  methodical  sections  as  lacking. 

The  question  seems  to  me  to  gain  clearness  if  we  distinguish  between 
pluriglandular  insufficiency  or  pluriglandular  syndromes  on  the  one  hand 
and  multiple  ductless  glandular  sclerosis  on  the  other,  for  the  existence  of  a 
pluriglandular  syndrome  does  not  signify  the  existence  of  a  multiple  ductless 
glandular  disease.  On  the  basis  of  what  I  have  already  written,  I  must 
assume  that  the  pluriglandular  syndrome  comes  about: 

1.  Through  physiological  correlation. 

2.  Purely  functionally  through  influencing  on  the  part  of  the  vegetative 
centers. 

I  have  gone  more  intimately  into  the  question  of  the  latter  factor  in  the 
consideration  of  the  vegetative  neuroses.  As  far  as  the  physiological  corre- 
lation is  concerned,  it  seems  to  me  that  it  affords  no  ground  for  a  confusing 
of  the  sharply  delimited  disease  pictures  of  the  individual  ductless  glandular 
diseases.  Let  us  first  consider  the  diseases  due  to  deficiency.  That  in 
myxedema  the  activity  of  the  glands  of  generation  is  diminished  or  that 
in  hypophysial  dystrophy  there  occurs  even  marked  degeneration  of  the 
sexual  glands  belongs  to  the  disease  pictures  themselves.  On  account  of 
this  no  doubt  is  cast  on  the  view  that  in  the  first  case  the  thyroid  gland  is 
the  central  figure  of  the  pathogenesis,  in  the  second  the  hypophysis.  The 
disease  pictures  which,  however,  we  assume  as  the  result  of  a  pathological  cor- 
relation already  belong  to  multiple  ductless  glandular  diseases:  I  refer  once 
more  to  the  simultaneous  degenerative  lesions  of  the  thyroid  gland  and  the 
glandular  hypophysis,  of  the  thyroid  gland  and  the  insular  apparatus  of  the 
pancreas,  etc.  The  pathological  correlation  finds  its  most  complete  ex- 
pression in  that  clinical  picture,  well  characterized  in  a  symptomatological 
respect,  which  I  have  termed  multiple  ductless  glandular  sclerosis. 

Undoubtedly  more  complicated  are  the  relations  in  the  hyperfunctional 
diseases — not  so  very  much  in  Basedow's  disease.  Although  in  this  condi- 
tion we  may  acknowledge  a  functional  increase  of  the  chromaffin  tissue, 
this  is  secondary  and  well  enough  explained  by  physiological  correlation. 
That  long-continued  oversaturation  of  the  body  with  thyroid  gland  secretion 
may  give  rise  to  disturbances  of  the  functions  of  the  sexual  glands  is  not 
at  all  remarkable,  only  the  significance  of  the  thymus  hyperplasia  is  as  yet 
unclear.  But  on  this  account,  not  to  wish  to  consider  Basedow's  disease 
as  a  clinical  entity  seems   to  me  incomprehensible.     Sooner  could  aero- 


THE    DUCTLESS    GLAXDS    AXD    COXSTITUTIOX  45 

megaly  be  regarded  as  a  pluriglandular  disease;  this  is  not  new,  however,  but 
was  already  mentioned  by  Pineles  in  his  classical  work.  In  addition  to 
hyperplasia  of  the  hypophysis,  we  not  rarely  find,  in  acromegaly,  symptoms 
of  Basedow's  disease,  in  the  later  stages  eventually  symptoms  similar  to 
myxedema,  also  to  diabetes,  and  in  the  most  cases,  as  is  known,  premature 
disturbances  on  the  part  of  the  glands  of  generation,  which  may,  however, 
be  sometimes  preceded  by  temporary  increase  of  their  function.  Of  late 
years,  too,  have  been  issued  reports  as  to  hyperplasia  of  the  suprarenal 
cortex;  briefly,  in  acromegaly  there  comes  about  a  pluriglandular  hyper- 
plasia of  the  ductless  glandular  system,  which  mostly  is  rapidly  foUowed  by 
a  degeneration  and  exhaustion.  This,  however,  likewise  belongs  to  the  dis- 
ease picture  of  acromegaly,  and  on  this  account  we  would  hardly  be  likely 
to  confuse  a  Basedow's  disease  with  an  acromegaly. 

These  pluriglandular  disturbances  are  found  much  more  pronouncedly 
in  many  cases  of  gigantism.  Here  the  hyperplasia  would  seem  to  be  a  par- 
tial manifestation  of  an  abnormal  predisposition  to  growth  of  the  entire  body. 

Concerning  the  therapeutic  results  of  opotherapie  mixte,  that  have  been 
hailed  with  such  enthusiasm,  they  must  be  regarded  with  much  scepsis,  espe- 
cially in  so  far  as  they  are  concerned  with  the  trophoneuroses  of  the  vege- 
tative nervous  system.  However,  I  do  not  wish  to  deny  the  justification 
for  this  therapy  in  combined  diseases  due  to  absence  [Ausf all] . 

Desirable  seems  to  me  a  sharper  delimitation  of  the  ductless  glandular 
diseases,  not  only  from  the  vegetative  neuroses,  but  also  from  certain  vege- 
tative disturbances.  The  regarding  of  chondrodystrophy  as  a  ductless 
glandular  disease  has  been  practically  done  away  with.  ^Mongolism  is  re- 
garded to-day  as  a  product  of  degeneration,  in  which  a  thyogenic  component 
is  associated,  at  most.  Lately,  true  dwarfism  has  been  regarded  as  a  disease 
due  to  deficiency  of  the  hypophysis,  a  view  that  will  hardly  meet  with  general 
acceptance.  Most  obstinate  are  the  attempts  to  obtain  a  place  among  the 
ductless  glandular  diseases  for  true  infantihsm.  In  true  infantihsm  the 
organism,  on  account  of  a  damage  in  fetal  or  postfetal  life,  does  not  progress 
beyond  the  child  stage  of  development.  In  this  remaining  behind,  the 
ductless  glandular  system  participates,  as  well  as  the  central  nervous  system 
and  every  other  organ  of  the  body.  There  are,  however,  no  indications  that 
the  ductless  glands  functionate  deficiently,  which  dictum  holds  also  for  the 
sexual  glands — these  functionate,  but  only  as  in  the  child  organism;  if  they 
were  not  to  functionate,  the  genitalia  and  dimensions  of  the  body  would  be 
eunuchoid,  but  not  infantile. 

The  Ductless  Glands  and  Constitution 

After  the  above  attempts  to  delimit  the  ductless  glandular  diseases  from 
the  disease  groups  that  are  related  to  them,  I  would  add  a  few  remarks  as  to 
the  significance  of  the  ductless  glandular  system  for  the  total  constitution  of  the 


46  GENERAL    PART 

body.     Martius  says  "die  Gesamtkonstitution  ist  die  Summe  der  Teilkon- 
stitutionen"  [the  total  constitution  is  the  sum  of  the  partial  constitutions]. 
I  might  suppose  that  from  the  study  of  the  physiology  and  pathology  of  the 
ductless  glandular  system  we  have  obtained  a  deeper  insight  into  one  of 
these  partial  constitutions.     At  all  events  we  must  not  accept  the  ductless 
glandular  system  for  itself  alone,  but  must  regard  as  a  constitutional  com- 
ponent the  ductless  glands  as  vegetative  organs  together  with  the  nervous 
system  regulating  their  functions.     Wiinderlich  distinguishes  a  strong,   an 
irritable,  and  a  lax  constitution.     This  classification  seems  also  to  apply  to 
those  components  of  the  general  constitution  whose  differentiation  we  are 
at  present   concerned   with.     We   can  group   individuals  into   those   with 
stabile,  those  with  dcbile   and  those  with  labile,  vegetative  nervous  systems, 
and  individuals  with  stabile,  debile,  and  labile  ductless  glandular  systems. 
The  certain  degree  of  autonomy  that  is  an  attribute  in  general  of  the  duct- 
less glandular  system  has  as  a  sequel  the  fact  that  the  corresponding  partial 
constitutions  may  occur  separately;  the  intimate  relations  that  exist  between 
both  systems  would  lead  us  to  expect,  however,  that  they  are  to  be  very  often 
found  united  in  the  same  individual  or  that  where  one  is  present  the  other  is 
at  least  suggested.     As  the  hereditary  factor  is  very  prominent  in  both,  we 
find  them  in  the  most  diverse  variations  and  combinations  in  members  of  the 
same  family.     In  individuals  with  a  predisposition  to  a  debile  vegetative 
nervous  system  there  develop,  under  the  demands  that  life  makes  on  the 
organism,  an  asthenia  of  the  vegetative  organs  with  general  enteroptosis, 
sluggishness  of  evacuations,  anomalies  of  the  secretion  of  gastric  juice,  de- 
pressive mental  attitude,  in  short  the  features  that  are  an  expression  of  Stiller^ s 
asthenia.     In  the  individuals  predisposed   to  a  labile  vegetative  nervous 
system,  readily  accessible  to  irritations,  there  exists  a  tendency  to  neuras- 
thenia, hysteria,  and  the  vasomotor-trophic  neuroses.     It  seems  to  me  that 
this  classification  may  be  applied  in  the  smallest  detail  to  the  ductless 
glandular  system.     The  ductless  glandular  debile  individuals  are  those  in 
whom  there  is  not  only  a  small  functional  breadth,  but  perhaps  also  a  certain 
tendency  for  certain  diseases,  especially  for  infections,  or  a  slighter  resistance 
against  alcohol  or  against  certain  toxins  that  may  proceed  from  a  focus  of 
infection  somewhere  in  the  body.     To  me  the  most  interesting  are  the  duct- 
less glandular  labile  individuals.     These  are  individuals  who  several  times  in 
the  month  show  extraordinary  variations  in  the  body  weight,  or  those  in 
whom  the  thyroid  swelHng  that  occurs  normally  during  pregnancy  leads  to 
slight  manifestations  of  Basedow's  disease,  or  those  in  whom  a  strong  emo- 
tional  excitement  calls  forth   temporary  glycosuria,   or  perhaps   those   in 
whom  slight  symptoms  of  acromegaly  occur  during  pregnancy,  or  women  in 
whom  exist  marked  dysmenorrheic  distresses.     In  this  group  are  always  to 
be  found,  too,  some  symptoms  that  point  to  an  especial  lability  of  the  vegeta- 
tive nervous  system.     I  need  not  attempt  the  description  of  the  stabile  in- 


THE   DUCTLESS    GLANDS    AND    CONSTITUTION 


47 


dividuals.     They  are  those  with  an  enviable  equiUbrium  of  their  vegetative 
functions,  their  metaboHsm,  and  their  psyche. 

The  relationship  of  both  the  disease  groups  is  also  shown,  as  has  already 
been  mentioned,  in  the  fact  that  they  sometimes  occur  combined  or  alter- 
nating in  the  members  of  one  family.     I  here  submit  an  example : 

Grandfather 

(Obesity  and  Gout) 


Son  Daughter  Daughter 

(Slight   thyroid  (Slight    thyroid  (Slight    thyroid    glan- 

swelling,     later  glandular  swell-  dular    swelling,    mani- 

light      diabetes  ing,    climacteric  festations     of     hyper- 

with  light  Base-  psychosis,    light  thyrosis.) 
dow's       symp-  diabetes.) 
toms.) 


Son 

(Obesity.) 


i  / 

Granddaughter  Granddaughter 

(Severe   exuda-         (Obesity.) 
tive     diathesis, 
later  bronchial 
asthma.) 


i  1 

Granddaughter  Granddaughter 

(Pronounced  lability  of  (Likewise  lability 
the  ductless  glandular  of  the  ductless 
system,  great  varia-  glandular  system, 
tionsinthebody  wieght  migraine,  parox- 
during  pregnancy,  ysmal      tachycar- 

light  Basedow's  symp-  dia.) 
toms,    great    sensitive- 
ness against  cocaine.) 

I  would  consider  it  probable  that  such  family  trees  are  not  at  all  hard  to 
find,  at  least  they  do  not  occur  isolated,  but  readily  could  be  traced  in  the 
family  trees  of  famihes  with  diatheses. 

This  affords  me  the  opportunity  of  saying  a  few  words  with  regard  to 
the  significance  of  the  ductless  glandular  system  for  the  diatheses.  Accord- 
ing to  W.  His  we  understand  by  diathesis  an  individual,  congenital,  and 
often  inherited  condition,  which  consists  in  the  fact  that  physiological 
stimuli  call  forth  an  abnormal  reaction,  and  that  conditions  of  living,  that 
are  borne  without  harm  by  the  majority  of  the  race,  call  forth  conditions  of 
disease.  The  circumstance,  that  in  the  great  group  of  arthritic  diatheses,  as 
also  under  the  diatheses  of  pediatrics  and  dermatology,  there  are  found  con- 


48  GENERAL    PART 

ditions  that  we  regard  as  vegetative  neuroses,  shows  that  the  vegetative 
nervous  system  has  a  prominent  place  here.  Rapin  sees  also  in  a  familial  and 
inherited  lability  of  the  nervous  system  the  connecting  link  between  the  in- 
dividual diatheses.  In  this  connection  we  must  turn  our  attention  to  the 
ductless  glandular  system.  Actually  we  find  that  diabetes  and  obesity 
play  a  prominent  part  in  the  great  group  of  arthritism.  The  connection 
between  gout  and  the  ductless  glandular  system  is.  of  course,  at  first  hand  as 
yet  quite  unclear.  In  the  pathogenesis  of  the  spasmophilic  diathesis  we 
must,  even  with  the  use  of  the  utmost  reserve,  ascribe  some  significance  to 
the  parathyroid  glands.  Also  for  the  genesis  of  lymphatism  the  observations 
that  status  lymphaticus  is  regularly  associated  with  hypoplasia  of  the  chrom- 
affin tissue  cannot  be  quite  without  significance.  For  the  predisposition  to 
the  dermatoses  the  processes  in  the  sexual  sphere  are  of  importance,  as 
Bloch  emphasizes,  for  just  at  the  transitional  periods,  at  puberty  and  at  the 
climacteric,  certain  dermatoses  are  very  common,  and  others,  like  favus  or 
trichophytina.  disappear  with  the  beginning  of  puberty.  Here  the  ductless 
glandular  system  exerts  a  certain  influence  on  the  natural  immunity. 

A  very  much  older  observation  concerns  the  known  inclination  of  dia- 
betics for  furunculosis.  and  the  great  vulnerability  of  their  tissue.  This 
may  be  shown  experimentally:  it  is  known  that  after  extirpation  of  the  pan- 
creas it  is  not  easy  to  obtain  a  reactionless  healing  of  the  laparotomy  wound. 
Bloch  infected  the  skin  of  dogs  with  yeast  before  and  after  the  extirpation 
of  the  pancreas  and  found  that  the  aftection  was  much  worse  in  the  dogs 
without  a  pancreas.  The  fact  in  itself  cannot  be  gainsaid,  but  as  yet  we 
are  without  any  deep  insight  into  the  nature  of  this  disease  susceptibility. 

As  may  be  gathered  from  the  elucidation  of  the  idea  of  diathesis  through 
the  summarizing  "Referate"  [references]  of  His.  Pfaundler,  and  Bloch,  we 
are  dealing  in  the  diathesis  not  with  sharply  circumscribed  disease  pictures, 
but  with  an  exceedingly  manifold  disease  susceptibility  resting  on  as  yet 
hard  to  define  factors;  alterations  in  the  function  of  the  ductless  glands 
constitute  only  one  of  these  factors;  in  a  theoretical  sense  I  would  not, 
however,  estimate  this  factor  as  of  slight  importance,  for  if  we  see  in  the 
interest  that  physicians  have  taken  in  the  question  of  diathesis  a  sort  of 
resurrection  of  the  old  humoral  pathology,  and  if  we  seek  in  an  altered  blood 
admixture  and  the  consequent  changing  of  the  tissues  the  cause  of  the 
tendency  to  disease,  we  find  that  the  little  that  the  study  of  the  ductless 
glandular  diseases  has  afforded  for  the  knowledge  of  diathesis  has  up  to  the 
present  first  furnished  an  idea  as  to  the  genesis  of  this  alteration  of  the 
blood  admixture  and  the  tissue  changes  that  follow  it. 

Finally  a  few  words  as  to  senility.  H  or  shy  first  pointed  out  that  the 
alterations  of  the  skin  and  other  tissues  that  occur  in  old  age.  especially  the 
increase  of  the  connective  tissue,  have  a  certain  similarity  with  those  that 
occur  after  extirpation  of  the  thyroid  gland,  and  that  on  the  other  hand 
localization  of  the  fat  deposits  in  old  age  is  similar  to  that  in  eunuchoidism. 


ADDENDUM  49 

In  a  detailed  study  Lorand  has  upheld  the  idea  that  the  degeneration  of 
the  ductless  glandular  system  is  chiefly  the  cause  of  senility.  I  would  not 
concur  with  this,  so  far  as  physiological  old  age  is  concerned,  but  believe 
much  more,  as  does  also  Ewald,  that  the  ductless  glandular  system  like  every 
other  organ  participates  in  the  involution  of  old  age.  There  is,  on  the  other 
hand,  a  pathological  old  age,  setting  in  prematurely  or  associated  with  dis- 
tinct accentuation  of  the  cachexia.  The  premature  senility  which  develops 
in  most  of  the  diseases  due  to  giving  out  of  function,  and  especially  in  mul- 
tiple ductless  glandular  sclerosis,  makes  intelHgible  to  me  the  fact  that 
degeneration  in  the  ductless  glandular  system  may  be  one  of  the  causes 
of  pathological  age. 

Addendum 

With  regard  to  what  has  been  written  in  toto,  it  may  be  said  that  the 
author's  views  respecting  the  grouping,  the  reciprocal  action,  etc.,  of  the 
ductless  glands,  and  their  effects  on  the  various  organs  and  systems  of  the 
body,  are  sound.  On  the  whole  they  seem  to  be  somewhat  in  advance  of 
the  general  conception  in  America  of  the  purport  and  scope  of  the  ductless 
glandular  apparatus,  at  least  in  regard  to  their  deliniteness.  There  seems 
to  be  a  tendency  among  some  recent  investigators  to  claim  too  much  for  the 
ductless  glandular  system  and  to  jump  to  conclusions,  attributing  effects  to 
the  system  of  endocrine  organs  that  might  just  as  well  be  explained  by 
metabolic  processes  that  are  general,  or  that  are  part  of  constitutional  fac- 
tors at  least  one  step  removed  from  purely  internal  secretory  activities. 

The  author's  chapter  on  ductless  glands  and  constitution  has  the  tend- 
ency to  counterbalance  this  drift.  Here  the  various  ductless  glandular 
constitutional  states  are  considered  as  part  of  a  "total  constitution,"  which 
is  made  of  factors  that  mutually  influence  each  other,  including  the  ductless 
glandular  system.  If  to  the  modern  mind  such  an  attempt  to  revive  the 
idea  of  "constitution"  and  its  sister  conception  "diathesis"  savors  too 
much  of  the  old  humoral  pathology  (which  by  the  way  in  its  serological 
form  has  led  or  will  lead  to  a  later  chemical  aspect  of  the  subject  which  will 
perhaps  be  all-embracing  so  far  as  relation  between  cell  and  tissue  juices  is 
concerned),  it  must  not  be  forgotten  that  "constitution"  itself  represents 
but  one  factor  of  a  far  more  extensive  subject — heredity,  a  subject  that  in 
its  last  analysis  resolves  itself  again  into  factors  that  are  mechano-chemical, 
and  perhaps  is  part  dependent  on  the  activities  of  just  these  ductless  glands. 

The  Abderhalden  reaction  has  already  furnished  results  with  regard 
to  the  reciprocal  activities  of  the  various  ductless  glands.  To  the  editor's 
mind  it  would  seem  that  the  importance  of  the  significance  of  the  Abder- 
halden reaction  (in  general,  not  simply  the  pregnancy  test)  has  not  as  yet 
been  sufficiently  realized,  at  least  in  this  country.^     That  its  basic  principle, 

^  Much  work   has  recently  been  done  with  the  Abderhalden  reaction,  especially  in  the  field 
of  nervous  and  mental  disease.     Remarkably  striking  have  been  the  labors  of  Fauser  and  his 
followers,  in  the  Abderhalden  diagnosis  of  dementia  precox      I  shall  not  enter  into  this  matter 
4 


50  GENERAL    PART 

the  formation  of  ferments — chemical  substances — for  the  sphtting  up  of 
alien  or  other  proteids,  as  a  matter  of  "Abwehr,''  defense,  is  a  biological 
phenomenon  at  the  basis  of  life  itself,  and  it  will  be  indeed  strange  if  this 
principle,  capable  as  it  is  of  exact  chemical  demonstration,  does  not  yield 
practical  results  far  in  advance  of  present  indications. 

The  matter  of  "Abwehr"  leads  us  to  two  other  so-called  discoveries  of 
recent  years — the  Freudian  theory  of  the  genesis  and  treatment  of  hysteria 
and  allied  neuroses  and  the  so-called  ''kinetic  theory"  of  Crile.  Of  these 
the  latter  merits  discussion  here  because  of  its  direct  relation  with  the  duct- 
less glandular  diseases,  and  the  former  because  of  the  relation  of  the  various 
neuroses  (and  even  psychoses)  to  the  ductless  glandular  system.  It  is  a 
pity  that  Crile  has  not  as  yet  (September,  1914)  published  the  results  of 
his  experiments  in  toto  and  in  detail,  as  much  of  what  he  claims  for  his  theory 
(based  as  it  is  on  painstaking  examination  of,  among  other  objects,  40.000 
nerve  cells)  seems  to  be  substantiated  by  older  and  more  recent  theories  of 
the  central  nervous  origin  of  such  ductless  glandular  conditions  as  Basedow's 
disease  and  diabetes  mellitus.  {Crile  will  be  mentioned  again  in  the  ad- 
dendum to  the  chapter  on  Basedow's  disease.) 

With  regard  to  Freud,  I  have  been  anticipated  in  what  I  wished  to  say 
by  dishing;  as  I  consider  the  matter  very  well  expressed  by  that  author^ 
I  shall  quote  in  extenso  passages  from  one  of  his  works: 

"The  pituitary  body  and  the  germinal  glands  appear  to  be  protagonists. 
Hypophysial  insufficiency  and  a  lowering  of  the  activity  of  the  reproductive 
functions  go  hand  in  hand,  and  in  some  of  our  examples  of  hypoplasia, 
glandular  feeding  has  unquestionably  led  to  a  restoration  of  potentia.  The 
reverse  is  probably  also  true,  for,  as  stated,  a  libidinous  tendency  often  ac- 
companies states  of  secretory  hyperplasia,  and  certain  experiments  under- 
taken with  Dr.  Emil  Goetsch  have  indicated  that  feeding  pituitary  extracts 
to  preadolescent  animals  leads  to  a  precocious  ovulation  and  spermato- 
genesis. These  observations,  coupled  with  the  knowledge  that  secretory 
discharges  from  the  hypophysis  may  be  elicited  through  the  sympathetic 
nervous  system,  suggest  that  the  liberation  of  a  chemical  messenger  may 
account  for  the  recognized  effect  of  the  emotions  upon  the  sexual  sphere." 

"It  is  plain  that  the  two  intracranial  glands,  hypophysis  and  epiphysis, 
normally  exercise  a  remarkable  influence  not  only  upon  the  nutrition  and 
skeletal  growth,  but  also  upon  the  sexual  sphere,  and  it  is  not  a  matter  for 
surprise  that  in  the  presence  of  a  definite  pathological  derangement  of  either 
of  these  structures  which  dates  from  childhood,  mentalitv  should  be  so  modi- 


here  but  refer  the  reader  to  the  bibliography  appended  to  Abdcrhalden's  Abwehrfermente  des 
tieris  chen  Organismus,  etc.,  or  to  that  at  the  end  of  Orion  s  article  (Am.  J.  Insanity,  vol.  71, 
iQISj  P-  573)-  Allusions  to  the  Abderhalden  reaction  will  be  found  in  certain  of  the  addenda 
to  the  chapters  of  the  present  work. — Editor. 


ADDENDUM  5 I 

fied  as  to  produce  peculiar  if  not  defective  individuals  when  measured  by  the 
standard  of  the  average. 

"With  this  conception  we  may  find  some  physiological  or  pathological 
basis  for  what  is  regarded  by  many  as  a  psychotherapeutic  phantasy;  for 
the  various  neuroses  and  asthenias  may  arise  primarily  as  the  result  of  some 
disturbance  of  internal  secretion  which  proves  the  way  for  the  dreams, 
symbolisms,  neurograms  and  other  acrostical  manifestations  dissected  by 
the  psychoanalyst.  If  therefore  we  are  to  swallow  the  Freudian  doctrines 
whole — a '  difficult  morsel  for  many — and  are  to  interpret  hysteria  and  the 
psychoneuroses  solely  as  the  resultant  of  early  mental  conflicts  and  com- 
promises between  the  libido  and  its  repressions,  it  will  be  easily  seen  that  any 
secretory  duration  which  on  the  one  hand  excites,  or  on  the  other  diminishes, 
sexual  activities  must  be  an  important  element  in  modifying  the  terms 
affecting  the  ultimate  compromise. 

"We  have  of  course  been  considering  extreme  examples,  but  is  quite 
probable  that  the  psychopathology  of  everyday  life  hinges  largely  upon 
the  effect  of  ductless  gland  discharges  upon  the  nervous  system.  This  is 
particularly  worthy  of  consideration  in  the  study  of  child  psychology  in 
its  relation  to  puberty  and  adolescence,  especially  in  those  individuals  in 
whom  there  is  some  underlying,  possibly  inherited,  functional  deviation  in 
the  chemistry  of  the  internal  secretion.  At  any  age,  however,  in  the  pres- 
ence of  some  ductless  gland  irregularity,  which  in  chemically  speaking  more 
stable  individuals  would  be  transient,  may  produce  secretory  disturbances, 
characterized  by  more  or  less  chronicity." 

"It  is  hoped  that  some  serological  test,  possibly  in  the  direction  of 
Abderhalden's  investigations  on  the  serodiagnosis  of  pregnancy,  will  serve 
to  give  as  a  chemical  reaction  of  diagnostic  value,  at  least,  for  states  of  over- 
activity of  individual  glands  .  .  .  and  we  possibly  may  come  to  attach  an  im- 
portance to  the  findings  of  pathological  serology  far  greater  than  that  which  in 
the  past  we  have  given  to  the  cytological  changes  shown  in  the  microscope." 

It  was  part  of  the  philosophy  of  the  ancients  to  explain  change  in  matter 
as  due  to  the  "love"  of  the  elements.  We  still  speak  of  chemical  affinities. 
Nowadays  we  resolve  love  into  its  chemical  constituents.  All  of  which 
makes  not  one  whit  less,  but  rather  much  more  wonderful,  the  phenomena 
manifested  by  the  various  bindings  together  of  atoms. 

Thus  is  the  Freudian  theory  placed  on  a  materialistic  basis  with  re- 
gard to  the  genesis  of  certain  of  the  epiphenomena  of  some  of  the  neuroses. 
That  the  underlying  factor  of  heredity  governs  here  the  constitution,  pre- 
disposing either  the  ductless  glandular  or  the  nervous  factor  or  both  to  ab- 
normal action,  there  can  be  no  doubt.  One  thing  at  least  we  may  be  assured 
of:  without  internal  secretion,  no  thoughts.  The  fact,  however,  that  the 
nervous  tissue  seems  to  be  especially  susceptible  to  the  influence  of  the 


52  GENERAL    PART 

internal  secretions  of  what  is  ordinarily  known  as  the  ductless  glandular 
system  does  not  preclude  its  influencing  by  products  of  cellular  activity 
elaborated  in  the  course  of  diseases  that  have  nothing  to  do  with  the  ductless 
glandular  system  (I  am  indebted  for  this  idea  to  remarks  by  McCarthy,  in 
an  extempore  address)  or  in  which,  as  in  the  infectious  diseases,  the  ductless 
glandular  system  is  influenced  only  indirectly.  This  subject  last  mentioned, 
that  of  ductless  glandular  aft'ection  in  the  course  of  infectious  disease  has  been 
taken  up  especially  hy  Sajous,  to  whom  we  are  indebted  so  much  for  attract- 
ing our  attention  to  the  importance  and  scope  of  ductless  glandular  affections. 

What  is  especially  noticeable  in  the  ductless  glandular  diseases  is  the 
employment  of  chemical  substances  or  glandular  extracts  in  their  diagnosis — 
a  use  for  these  substances  or  extracts  that  independently  of  the  ameliorative 
effect  is  perhaps  new  in  the  art  of  diagnosis,  and  that  may  perhaps  mark 
the  beginning  of  a  new  science,  that  of  pharmacodiagnosis. 

Sajous  has  recently  published  a  resume  of  his  conclusions  with  regard  to 
the  function  of  the  various  constituents  of  the  ductless  glandular  system. 
This  resume  approaches  first  principles  to  a  greater  extent  than  any  of 
Faltas  conclusions,  and  is  interesting  as  furnishing  a  basis  of  comparison 
with  the  results  of  Faltas  work.  Sajous  maintains  that  the  thymus  gland 
supplies  to  all  tissues  the  excess  of  phosphorus  in  organic  combination 
(possibly  as  nucleins)  required  to  build  up  cell-nucleins  while  the  animal  or- 
ganism is  developing.  The  thyroparathyroid  secretion  (thyroidase)  sensitizes 
these  nucleins  to  the  action  of  oxygen.  The  adrenal  secretion  (through  its 
catalytic  ferment,  adrenoidase)  endows  the  blood  with  its  oxygenizing  prop- 
erties. The  pancreas  supplies  the  ferments  which  in  the  intestinal  canal  and 
nutritional  leucocytes  change  food  materials  into  products  harmonious  to, 
and  for  the  building  up  of,  tissue  cells,  that  is,  for  the  anabolic  phases  of 
metabolism.  The  same  pancreatic  ferments  also  carry  on  the  catabolic 
phase  of  metabolism.  All  endogenous  and  exogenous  substances  that  are 
not  appropriate  for  tissue-building — bacteria,  toxins,  toxic  wastes,  toxic 
venoms,  etc.,  are  subjected  in  the  phagocytic  leucocytes,  the  tissue  cells, 
the  lymphatic  system  and  the  blood  plasma  to  the  catabolic  phase  of 
metabolism,  which  serves  to  convert  them  into  eliminable  end-products. 

Crile  {G.  II'.).  The  kinetic  system,  Cleveland  M.  J..  X'ol.  XII,  Xo.  4,  October,  1913, 
p.  665,  associated  with  which  is  : 

Hitchings  (F.  IF.),  Sloan  (H.  G.),  and  Austin  (J.  B.).  Laboratory  studies  of  the  brain 
and  the  adrenals  in  response  to  specific  stimuli.  Ibidem,  pp.  684-691. 

Crile  (G.W.)  and  Lower  (W.  E.).    Anoci-association.     \V.  B.  Saunders  Co.,  Phila.,  1914. 

Cushing  (H.).  Psychic  disturbances  associated  with  disorders  of  the  ductless  glands. 
Am.  J.  Insanity  No.  5,  191 2,  special  number,  pp.  965-990. 

Sajous  (C.  E.  de  M.).  Among  other  articles:  Hypoadrenia  as  a  cause  of  death  in  in- 
fections and  its  treatment.  INIonthly  Cyclopaedia  and  Medical  Bulletin,  \'ol.  IV,  191 1, 
pp.  725-729.  Also  his  Internal  secretions  and  the  principles  of  medicine,  5th  edition, 
Phila.,  F.  A.  Davis  and  Co.,  191 2. 

Sajous  (C.  E.  de  M.).  The  theory  of  the  internal  secretions.  The  Practitioner.  Feb., 
1915,  pp.  180-197. 


CHAPTER  II 


THE  DISEASES  OF  THE  THYROID  GLAND 


Anatomy  and  Embryology. — The  thyroid  gland  of  man  has  the  shape  of  a 
butterfly.  The  two  lobes  lying  on  the  lateral  surfaces  of  the  trachea  and 
larynx  are  joined  together  by  the  isthmus,  which  is  sometimes  prolonged 
for  a  certain  distance  superiorly  as  the  so-called  processus  pyramidalis. 
The  weight  of  the  thyroid  gland  in  the  adult  approximates  36-50  gm. 

The  isthmus  is  developed  from  an  unpaired  evagination  from  the  ventral 
wall  of  the  head-gut  cavity.  In  many  of  the  lower  animal  classes  the  con- 
nection with  the  head-gut — the  ductus  thyroglossus — is  retained.  Here  the 
thyroid  is  a  gland  with  external  secretion.  In  the  higher  animal  classes  the 
ductus  thyroglossus  obliterates  early.  Con- 
cerning the  development  of  the  lateral  lobes 
opinions  to-day  are  still  divided.  It  is  safe 
to  say  that  a  portion  of  the  lateral  thyroid 
gland  rests  are  developed  through  evagina- 
tion from  the  median  rest.  It  is  further 
certain,  according  to  the  investigations  of 
Erdheim  and  Schilder,  that  the  so-called  post- 
branchial  bodies,  that  originate  from  the 
ventral  wall  of  the  fourth  branchial  pouch, 
can  give  rise  to  thyroid  gland  tissue,  for  in 
the  cases  of  thyroaplasia  in  which  the  me- 
dium rests  of  the  thyroid  remain  rudimentary, 
the  indifferent  rests  of  these  bodies  regularly 
contain   some  thyroid  gland  follicles.     Only 

uncertain,  therefore,  is  to  what  extent  under  normal  conditions  the  lateral 
rests  of  the  thyroid  gland  take  part  in  the  formation  of  the  lateral  lobes. 
To  aid  the  better  comprehension  of  the  subject,  I  subjoin  the  accompany- 
ing sketch  taken  from  the  work  of  Maurer  in  which  is  shown  the  devel- 
opment of  the  parathyroid  and  the  thymus  glands. 

The  rudiments  of  the  thyroid  wander  downward  with  the  heart.  Along  the  entire 
tract  from  the  root  of  the  tongue  to  the  aorta  may  be  found  cut-off  portions  of  thyroid 
glandular  tissue,  accessory  thyroids,  which  may  give  occasion  to  the  formation  of  ab- 
normally situated  goiters  (tongue  goiters,  retrosternal  goiters,  etc.). 

The  thyroid  is  remarkably  well  vascularized.  It  consists  histologically 
of  follicles  lined  with  cubical  or  cylindrical  epithelium,  which  for  the  most 

S2, 


T-m3 


Fig.  i—Tr  =  Thyroid;  /,  //, 
///,  IV  =  pharyngeal  pouches;  £3^4 
=  rudiments  of  the  parathyroid 
glands;  p  =  postbranchial  bodies; 
Tm  =  rudiment  of  thymus. 


54  THE    DISEASES    OF    THE    THYROID    GLAND 

part  are  filled  with  colloid.  This  contains  the  specific  secretion,  which,  ac- 
cording to  the  need,  gets  into  the  circulation,  probably  through  the  lymph 
paths.  Fr.  Kraus  therefore  designates  the  thyroid  a  reserve  or  storage 
gland.  The  thyroid  is  signalized  by  an  especially  high  contents  of  iodine; 
in  the  formation  of  the  specific  secretion,  which  is  bound  to  an  albuminous 
body  thyroglobulin. 

We  may  divide  the  diseases  of  the  thyroid  gland  into  those  which  for  the 
most  part  do  not  especially  restrict  its  functions,  but  chiefly  produce  local 


Fig.  4. — Normal  th\'roid  gland  with  colloid  formation. 


symptoms,  and  those  the  principal  symptoms  of  which  depend  on  the 
alteration  of  the  internal  secretory  function.  To  the  first  belong  certain 
forms  of  the  goiters,  the  tumors  and  the  inflammations.  The  goiters  are 
discussed  in  the  chapter  on  the  cretinic  degeneration. 

Timiors  of  the  Thyroid  Gland.— Among  the  tumors  are  found  most  com- 
monly adenoma,  carcinoma,  and  sarcoma.  The  simultaneous  occurrence  of 
sarcoma  and  adenoma  in  the  thyroid  gland  has  been  reported  {Saltykow 
gives  the  literature).  The  tumors  mentioned  all  show  a  great  tendency 
toward   the  formation  of  metastases.     In  carcinoma,  bone-metastases  are 


IXFL  AMM  ATIOX  5  5 

especially  frequent,  especially  in  the  bones  of  the  skull  and  in  the  sternum; 
in  sarcoma,  metastases  are  frequently  found  in  the  lung.  The  metastases 
of  adenocarcinoma  of  the  thyroid  gland  contain  not  inappreciable  amounts 
of  iodine.  Gierke  reports  two  cases  of  carcinoma  of  the  thyroid  vd\h  metas- 
tases in  the  vertebral  column.  In  the  case  of  En'ald.  the  highly  decomposed 
primary  adenocarcinoma  of  the  thyroid  was  iodine  free;  the  metastases  in 
the  lungs  and  lymph-glands  contained  iodine.  The  decision  as  to  whether  an 
adenoma  of  the  thyroid  is  malignant  or  benign  is  often  very  difficult  (v. 
Eiselsherg).  ^Microscopically  metastases  may  appear  as  gelatinous  goiters, 
and  yet  the  very  presence  of  metastases  may  in  itself  be  regarded  as  the  sign 
of  malignancy.  Sometimes  the  metastases  when  examined  microscopically 
show  a  formation  similar  to  carcinoma. 

On  account  of  the  proximity  to  many  important  organs  Ttrachea,  esopha- 
gus, sympathetic,  vagus,  etc. J.  tumors  of  the  thyroid  not  infrequently  cause 
very  manifold  local  manifestations,  which  will  not  be  discussed  further  at 
this  place.  They  may  also  give  rise  to  alterations  in  the  thyroid  function. 
Symptoms  of  deficiency  [of  secretion]  are  relatively  rare,  and  it  may  then 
happen  that  the  symptoms  of  myxedema  retrogress  when  metastases  de- 
A"elop  (v.  Eiselsherg)  or  when  accessory  thyroids  begin  to  grow.  This  may 
even  occur  when  the  metastases  have  become  degenerated  carcinomatously. 
Indeed  v.  Eiselsherg  found  in  the  metastases  in  such  a  case  folHcles  still  filled 
with  colloid.  Xot  so  very  rarely  malignant  tumors  of  the  thyroid  gland 
take  on  the  characteristics  of  Basedow's  disease.  Saltier  has  collected 
sixteen  such  cases,  of  which  eleven  were  carcinomata.  and  three  sarcomata, 
while  in  two  the  character  was  not  determinable.  Indeed  the  Basedow's 
symptoms  may  not  appear  until  just  at  the  time  that  the  metastases  develop 
(J.  Lo-iVy  has  collected  the  literature;.  We  find  therefore  that  malignantly 
altered  thyroid  gland  tissue  may  not  only  affect  the  normal  function,  but, 
when  proliferation  is  rapid,  may  even  lead  to  hyperfunction.  The  inter- 
pretation of  the  symptoms  of  Basedow's  as  hypoth}Tosis  (Minnich)  is  not 
to  be  regarded  as  correct. 

Inflammations  of  the  Thyroid  Gland. — We  distinguish  between  thyroi- 
ditis and  strumitis.  The  first  is  A-ery  much  rarer,  as  apparently  the  normal 
thyroid  shows  little  tendency  for  inflammatory  processes,  which  has  also  been 
determined  experimentally  on  animals.  In  thyroiditis,  too,  as  Jeanseline 
mentions,  the  termination  in  suppuration  is  much  rarer.  A  light  inflamma- 
tion of  the  thyroid  is  A'ery  often  an  accessory  phenomenon  of  acute  infections 
(Roger  and  Gamier.  Kashiivamura,  de  Quervain,  Sarhach,  and  others).  The 
histological  alterations,  which  consist  in  epithelial  desquamation  and  dis- 
appearance of  the  foHicles.  hyperemia,  etc.,  may  be  not  inappreciable  after 
scarlet  fever  and  variola,  and  also  after  other  infectious  diseases.  Thyroiditis 
is  not  uncommon  in  the  early  stages  of  s}^hilis  (according  to  Engel-Remiers 
in  56  per  cent,  of  casesj.     Slight  sclerotic  processes   are   often  present  in 


56  THE    DISEASES    OF    THE    THYROID    GLAND 

tuberculosis  and  in  severe  alcoholism.  Severe  inflammatory  processes  in 
the  thyroid  have  been  observed  after  typhoid  fever,  variola,  influenza, 
malaria,  puerperal  processes,  etc. ;  especially,  however,  after  angina  and  acute 
articular  rheumatism.  A  detailed  summary  of  the  literature  is  that  by  de 
Quervain.  The  primary  form  of  acute  thyroiditis  which  does  not  go  on  to 
suppuration,  was  first  described  by  Mygind  and  more  recently  hy  de  Quervain 
in  a  very  thorough  report.  The  onset  for  the  most  part  is  sudden;  with 
evident  general  symptoms  and  fever  the  thyroid  gland  becomes  swollen, 
and  there  may  be  local  symptoms  of  pressure.  This  is  followed  by  severe 
pains  radiating  to  the  ear  and  throat;  the  climax  of  the  clinical  mani- 
festations is  for  the  most  part  soon  reached,  and  quickly,  or  more  or 
less  slowly  (lytically),  all  phenomena  subside.  The  histologic  picture  of 
the  thyroid  gland  is  in  many  respects  similar  to  that  of  the  Basedow  thyroid. 
Nothing  is  known  as  yet  as  to  the  causative  agent.  De  Quervain  recommends 
quinine  and  salicylic  acid  for  treatment;  we  must  operate  only  when  distinct 
fluctuation  is  present. 

Not  infrequently  the  inflammations  of  the  thyroid  gland  lead  to  pro- 
nounced disturbances  of  function.  In  a  case  of  Reinhold^s  symptoms  of 
Basedow's  appeared  after  influenza,  and  in  a  case  of  Gilbert  and  Gastaigne's 
in  the  convalescence  of  typhoid  fever.  Worth  mentioning  is  a  case  of  de 
Quervain's  with  recurring  articular  rheumatism  and  parallel  symptoms  of 
a  shght  thyroiditis  and  a  Basedow's.  A  pelt  reports  a  case  of  suppurative 
inflammation  of  a  goiter  of  the  tongue;  after  three  days  a  thyroiditis  made 
its  appearance,  to  give  rise  to  a  Basedow's  which  later  disappeared  almost 
entirely.  Also  the  clinical  primary  forms  may  be  associated  with  similar 
manifestations.  In  a  case  of  Breuer's  a  typical  Basedow's  developed  imme- 
diately after  an  acute  thyroiditis.  As  Mdbiiis  has  already  pointed  out,  we 
cannot  deny  for  these  observations  a  certain  significance  in  the  pathogenesis 
of  Basedow's  disease. 

Chronic  inflammatory  sclerosing  processes  commonly  lead  to  myxedema 
(see  later). 

I  may  not  leave  unmentioned  that  administration  of  iodine  serves  to 
increase  the  acute  thyroiditis  (Dunger).  In  the  case  of  Himmelheher  the 
thyroiditis  appeared  immediately  after  a  gynecologic  operation;  Himmelheher 
ascribed  to  the  iodine  absorbed  from  the  iodine  catgut;  after  high  fever, 
tachycardia,  acute  cardiac  dilatation,  and  delirium,  the  thyroid  swelling 
rapidly  disappeared. 

The  second  group  of  diseases,  those  in  which  the  internal  secretory  activity 
of  the  thyroid  gland  stands  in  the  foreground,  may  be  divided  into  diseases 
associated  with  increase  of  function  and  those  with  diminution  or  lack 
of  function.  I  begin  wuth  the  first,  as  they  are  better  adapted  to  give  an 
idea  of  the  normal  function  of  the  thyroid  gland. 


BASEDOW  S    DISEASE  57 

a.  Morbus  Basedow!  [Basedow's  Disease] — Hyperthyrcsis 

Synonyms. — Graves'  disease,  ]\Iorbo  di  Flajani  (Flajani's  disease),  goitre  exophthal- 
mique  [exophthalmic  goiter],  [Parry's  disease]. 

Historical. — In  the  year  1840,  v.  Basedow  first  thoroughly  described  three 
cases  of  the  disease  named  after  him.  Of  his  precursors,  is  especially  Graves 
to  be  mentioned,  who  in  1835  described  cases  of  the  disease  and  brought  it 
into  close  relationship  with  hysteria.  Since  the  time  of  v.  Basedow,  the 
views  as  to  this  disease  have  undergone  great  changes.  The  French  school 
regarded  it  as  a  neurosis,  while  Mohiiis  first  in  1886  assumed  an  abnormally 
increased  activity  of  the  thyroid  gland  as  the  cause,  and  pointed  out  the 
opposition  that  exists  between  this  disease  and  myxedema. 

Definition. — By  Basedow's  disease  we  understand  to-day  a  disease  which 
is  brought  about  principally  by  the  abnormally  increased  activity  of  the  thyroid 
gland.  This  is  almost  always  accompanied  by  an  enlargement  and  increased 
vascular  engorgement  of  the  thyroid  gland  and  leads  eventually,  through  the 
local  symptoms  conditioned  by  the  enlargement,  to  a  great  number  of  very  mani- 
fold manifestations,  of  which  especially  the  tachycardia,  the  well-known  eye 
symptoms,  the  tremor,  and  the  increase  in  metabolic  processes  are  the  most 
important.  Most  of  the  manifestations  are  to  be  explained  by  a  heightened 
condition  of  exciteme^it  of  the  vegetative  nerves.  Regular  and  very  manifold 
is  the  involvement  of  other  glands  of  internal  secretions,  which  for  the  most 
part  is  secondary.  The  syndrome  that  results  depends  therefore  not  upon 
the  degree  of  hyperf  unction,  but  on  the  constitution  of  the  individual  affected, 
that  is,  on  the  reaction  capability  of  the  ductless  glandular  apparatus.  The 
cause  of  hyperthyrosis  is  not  at  present  known.  The  possibility  exists  that  it  is 
conditioned  centrally,  and  that  many  symptoms  of  Basedow's  are  coordinate 
with  the  hyperthyroidism. 

Occurrence. — Basedow's  disease  is  rather  irregularly  distributed.  A 
careful  collection  as  to  its  occurrence  has  been  made  by  Sattler.  Most  of 
the  investigations  concerned  with  this  subject,  founded  in  part  on  a  very 
great  observation  material,  agree  that  the  classic  form  of  Basedow's  disease 
is  relatively  of  rare  occurrence  in  regions  where  goiter  is  endemic.  I  men- 
tion only  the  contributions  of  H.  Bircher,  Fr.  Kraus,  and  W.  Scholz.  In 
Germany,  for  example,  typical  cases  of  Basedow's  disease  are  very  much 
commoner  in  the  northern  parts;  they  seem  to  be  especially  numerous  in  the 
Russian  Baltic  provinces  (Kroug).  It  is  very  much  more  common  in 
the  female  sex  than  in  the  male.  In  Sattler' s  compilation  3120  of  the  3800 
cases  were  females.  It  is  not  very  common  in  childhood  (according  to  Sattler, 
out  of  3477  cases  only  184  were  in  children  under  fifteen  years  of  age).  Base- 
dow's disease  in  sucklings  appears  to  be  very  rare.  White  Clifford  has  re- 
ported a  case.  The  mother  of  the  child  had  also  previously  given  birth  to  a 
child  affected  with  symptoms  of  Basedow's.     In  the  case  described  there 


58  THE    DISEASES    OF    THE    THYROID    GLAND 

were  present  exophthalmus  and  a  struma,  which  microscopically  gave  a 
picture  very  similar  to  that  of  a  typical  Basedow's  struma.  Familial  oc- 
currence of  Basedow's  disease  is  not  at  all  uncommon.  E.  Frey  reports  a 
family  of  five  persons,  of  whom  four  suffered  with  Basedow's  disease.  Oster- 
reich  reports  likewise  a  family  in  which  ten  members  were  affected  with 
Basedow's  disease.  In  the  familial  type  we  find  not  rarely  many  mitigated 
hyperthyroses  or  hypothyroses.  In  addition  occur  neuroses  of  the  vegeta- 
tive nervous  system,  diabetes  mellitus,  and  even  psychoses.  Groher  publishes 
the  family  tree  of  such  a  family. 

Finally  it  should  be  stated  that  the  disease  is  met  with  in  animals  (dogs, 
cows,  horses),  in  isolated  cases. 

S5miptomatology. — The  pathologic  alteration  may  develop  in  a  pre- 
viously normal  thyroid  gland  or  in  a  thyroid  gland  degenerated  into  a  goiter. 
The  thyroid  gland  increases  in  volume,  becomes  soft  and  elastic,  through 
dilatation  of  the  blood-vessels,  and  becomes  very  vascular  through  new 
formation  of  blood-vessels;  under  circumstances  it  shows  expansive  pulsa- 
tions and  frequently  also  variations  in  volume,  paralleling  the  phenomena 
of  Basedow's  disease;  in  many  cases  the  apparently  not  enlarged  thyroid 
may  become  palpable  through  voluntary  increase  of  the  intrathoracic  pres- 
sure (Fr.  Kraus).  In  acute  cases  the  swelling  of  the  thyroid  may  appear  over 
night  and  even  lead  to  difticulty  in  breathing.  It  can  subside  just  as  sud- 
denly {Trousseau,  Mohiiis,  et  al.).  On  the  application  of  a  stethoscope  ap- 
plied to  the  gland,  we  can  for  the  most  part  hear  vascular  murmurs 
synchronous  with  the  heart  action  (Guttmann) .  The  hand  laid  on  the  gland 
feels  a  distinct  thrill;  we  can  diminish  the  size  of  the  gland  by  pressure. 
The  enlargement  of  the  gland  is  a  very  common  symptom,  yet  there  certainly 
do  occur  cases  with  distinct  manifestation  of  hyperthyrosis,  in  which  the 
enlargement  of  the  thyroid  gland  is  barely  demonstrable.  With  longer 
duration  of  the  disease,  the  consistence  of  the  gland  becomes  firmer. 

The  microscopical  examination  shows,  in  addition  to  increased  vasculariza- 
tion, rich  new  formation  of  epithelial  plugs  and  of  glandular  acini  which  later 
are  often  well  filled  with  desquamated  cells;  in  addition  there  are  accumu- 
lations of  lymphoid  cells  (Gibson,  Greenfeldt,  F.  Midler,  Luharsch,  ct  al.). 
Other  authors  (Farner  and  others)  find  less  typical  alterations,  although 
Askanazy  points  out  correctly  that  the  aberrant  findings  come  from  goiter 
districts;  it  may  therefore  be  assumed  that  in  these  cases  the  alterations  of 
Basedow's  have  developed  in  thyroids  that  are  already  degenerated.  Kocher 
designates  the  typical  Basedow  struma  as  a  struma  hyperplastica  paren- 
chymatosa  telangiectodes;  it  ordinarily  contains  no  colloid,  and  for  the  most 
part  is  poor  in  iodine. 

Among  the  cardiovascular  symptoms,  tachycardia  stands  in  the  fore- 
ground. For  the  most  part  there  exists  in  addition  an  especial  lability  of 
the  pulse.     It  may  happen  that  on  complete  rest  the  i)ulse  lies  only  slightly 


BASEDOW  S    DISEASE  59 

above  the  normal,  while  slight  psychic  emotions  or  physical  movements 
send  it  up  unusually  high.  Moreover,  there  exist  increased  strength  of 
the  heart  action  and  cardiac  palpitation.  The  patients  feel  the  heart  beat 
"up  to  the  throat."  The  cardiac  impulse  is  then  increased  and  broadened, 
and  the  thoracic  wall  is  strongly  agitated.  Very  often  broadening  of  the 
cardiac  dullness  occurs,  depending  more  commonly  on  cardiac  dilatation 
than  on  hypertrophy.  Frequently  there  are  accidental  systolic  murmurs. 
All  manifestations  on  the  part  of  the  heart  show  great  variations  that 
parallel  the  remainder  of  the  manifestations  of  the  course  of  the  disease. 

.  --v.r^'\r(^:-'  2'.;X 

Fig.  5. — Basedow  struma. 

In  the  fully  developed  form  of  the  disease  the  arteries  of  the  gland  often 
pulsate  very  strongly,  a  phenomenon  that  gives  these  cases  their  own  char- 
acteristic feature.  Especial  cases  may  even  go  as  far  as  a  penetrating  ve- 
nous pulse  in  the  thyroid  gland  or  to  a  pulsatory  shaking  of  the  head  {Mussefs 
sign)  or  to  choroid  pulse  (Becker).  Also  there  have  been  observed  marked 
beating  of  the  abdominal  aorta,  hepatic  pulsation,  and  splenic  pulsation 
(C.  Gerhardt) .  In  opposition  to  increased  heart  action  and  the  stormy  pulsa- 
tion in  the  neck,  the  radial  pulse  is  often  small  and  weak  and  the  blood- 
pressure  not  raised  or  even  slightly  diminished  (Spietkojf,  Donatli).  Height- 
ening of  the  blood-pressure  is  relatively  rare.     There  occurs  then  an  abnor- 


6o  THE    DISEASES    OF    THE    THYROID    GLAND 

mal  fall  from  center  to  periphery  {Fr.  Kraus)  which  is  explainable  by  the 
abnormal  laxity  of  the  tonus  in  the  peripheral  vessels.  Even  the  earlier 
observers  {Graves,  Stokes,  Hirsch,  Trousseau,  et  al.)  noticed  this  opposition 
between  the  increased  cardiac  activity  as  evidenced  on  the  part  of  the  heart 
and  the  vessels  of  the  neck,  and  the  relatively  slight  filling  of  the  peripheral 
vessels.  To  the  slight  tonus  of  the  peripheral  vessels  testify  also  the  often 
observable  reddening  of  the  face,  the  ears,  the  tips  of  the  fingers  and  the 
nail  matrices  {A .  Kocher) . 

So  much  for  the  clinical  observation.  Experimental  investigations  on 
the  action  of  the  thyroid  gland  secretion  upon  the  cardiovascular  apparatus 
are  very  numerous,  but  an  agreement  among  them  has  not  as  yet  been  ob- 
tained. Oliver  and  Schdjer,  Fenyvessy,  Haskovec,  and  others  found  after 
intravenous  administration  of  juice  of  thyroid  gland  sinking  of  the  blood- 
pressure  and  slowing  of  the  pulse.  Other  observers  found  no  action,  or 
acceleration  of  the  pulse-rate.  The  different  species  of  animals  behave 
differently,  v.  Cyon  found  that  on  the  cat  iodothyrin  acted  tonus-increasing 
on  the  vagus  and  the  depressor,  v.  Cyon  and  Oswald  found  the  same  true  of 
iodthyroglobulin,  while  iodine-free  thyroglobulin  is  inactive.  The  increase 
of  excitability  of  the  depressor  nerve  was  also  found  by  Asher  and  Flack. 
V.  Fiirth  and  Schwarz  consider  the  depressor  action  of  the  extract  not  specific 
for  the  thyroid  gland,  but  attribute  it  to  the  cholin  contained  in  the  extract. 
The  differences  in  the  results  are  to  be  explained  by  the  fact  that  on  the  in- 
travenous administration  of  thyroid  gland,  substances  that  influence  the 
cardiovascular  apparatus  are  also  introduced  that  have  nothing  to  do  with 
the  thyroid.  According  to  the  investigations  of  Falta,  Newburgh,  and  Xohel, 
the  feeding  of  thyroid  gland  produced  in  most  cases  an  increase  in  the  fall  of 
blood-pressure  from  center  to  periphery,  such  as  one  observes  in  Basedow's 
disease.  Tachycardia  is  present,  the  blood-pressure  taken  at  the  brachial 
remains  the  same  (blood-pressure  measurement  according  to  Rocci)  and  fall 
of  the  blood-pressure  in  the  periphery  (blood-pressure  measurement  accord- 
ing to  Gartner)}  On  the  administration  of  large  doses  of  thyroidin  there 
results  a  significant  fall  in  the  blood-pressure  (Pilez).  By  the  heightening  of 
the  fall  the  velocity  of  the  circulation  is  increased,  which  best  corresponds  to 
the  increased  oxygen  requirement. 

The  tachycardia  is  a  result  of  the  irritation  of  the  accelerator,  and  the 
slight  tonus  of  the  peripheral  vessels  is  a  result  of  irritation  of  the  vasodilator; 
the  dilation  of  the  thyroid-gland  vessels  is  the  result  of  the  irritation  of  the 
depressor  nerve,  as  irritation  of  the  root  of  the  depressor  nerve  calls  forth 
an  increase  on  the  blood-pressure  in  the  thyroid  {v.  Cyon).  Also  Asher  and 
Flack  found  that  the  excitability  of  the  depressor  nerve  is  increased  by  the 
internal  secretion  of  the  thyroid  gland.     The  increase  of  the  blood  stream 

^  An  exception  to  this  is  shown  only  by  diabetics,  who  show  an  increase  in  blood-pressure  (see 
chapter  on  pancreas). 


Basedow's  disease  6i 

favors  the  increased  output  of  secretion  and  thus  a  circulus  vitosus  is  es- 
tabhshed.  Perhaps  also  a  secondary  increase  of  the  activity  of  the  chrom- 
affin tissue  or  a  greater  sensitivity  to  adrenahn  of  the  organs  supplied  by 
sympathetic  nerves  is  associated  with  the  cardiovascular  symptoms  (tachy- 
cardia). The  facts  are  that  on  the  simultaneous  administration  of  thyroid- 
gland  secretion  and  adrenalin,  action  pulses  may  also  be  produced  in  animals 
(Kraus  and  Friedenthal) ;  v.  Cyon  attributes  to  a  simultaneous  irritation  of  the 
vagus  and  sympathetic,  and  to  the  fact  that,  according  to  Asher  and  Flack, 
the  thyroid-gland  secretion  may  increase  the  activity  of  adrenalin. 

The  eye  symptoms  may  be  expressed  in  different  degrees  of  intensity. 
Often  there  is  onlv  a  sliojhtiv  heightened  glitter  of  the  eve,  the  alterations 


Fig.  6. — Gaping  of  the  palpebral  fissures  in  Basedow's  disease. 

showing  only  on  very  exact  examination;  in  other  cases  occur  those  strik- 
ing alterations  that  Mobius  compares  with  those  of  the  facial  expression  of 
intensest  terror. 

As  an  example  I  shall  quote  the  following  case: 

Observation  I. — Anna  K.,  twenty-six  years  old.  For  about  two  months  cardiac  pal- 
pitations, conditions  of  excitement,  pains  in  the  cardiac  region,  sweats,  tremor,  and  en- 
largement of  the  neck. 

The  increased  width  of  the  palpebral  fissures  is  evident.  Protrusion  slight,  rare  blink- 
ing, thyroid  diffusely  enlarged,  weakly  elastic  vascular  murmurs,  tachycardia  up  to  361 
[sic.],i  blood  pressure  (Riva-Rocca)  100.  Increase  of  temperature  up  to  37.7°  C, 
alimentary  glycosuria  negative. 

^361  in  the  German  edition — probably  an  error  for  136. — Editor. 


62 


THE    DISEASES    OF    THE    THYROID    GL.\XD 


In  many  cases  the  development  of  the  eye  symptoms  comes  about  very 
gradually.  In  other  cases,  the  terrifying  alterations  may  develop  in  a  few 
days,  indeed  over  night.  We  should  distinguish  between  protrusion  and 
widening  of  the  palpebral  fissures.     In  fully  developed  cases  both  symptoms 


Fig. 


-Protrusion  of  the  eve-balls  in  Basedow's  disease. 


are  for  the  most  part  really  present  together.     The  protrusion  of  the  eye- 
balls is  well  seen  in  the  accompanying  illustration. 

Observation  II. — K.  I.,  fifty  years  old,  the  morbus  Basedowi  has  lasted  about  ten 
years,  tachycardia,  sweats,  formerly  profuse  diarrhea,  tremor,  formerly  marked  emacia- 
tion, and  high-grade  nervousness;  lately  condition  better,  for  years  a  stationary  condition. 

The  protrusion  of  the  eye-balls  is  explained  by  most  authors  by  an  in- 
creased fullness  of  the  orbital  \essels.     The  rapid  variations  in  the  intensity 


Basedow's  disease  63 

that  the  protrusion  of  the  eye-ball  shows  in  many  patients  have  led  to  this 
assumption.  The  essential  cause  is,  however,  an  abnormal  tonus  of  the 
Landstrom  musculus  palpebralis,  which  is  innervated  by  the  sympathetic. 
The  protrusion  may  be  produced  experimentally  by  electric  stimulation  of 
the  cervical  sympathetic  {Claude  Bernard).  The  protrusion  may  be  such 
a  high  grade  that  the  globe  becomes  displaced.  In  old  Basedow's  cases  the 
protrusion  remains  stationary,  which  may  be  explained  through  increased 
deposition  of  retrobulbar  fatty  tissue.  The  gaping  of  the  palpebral  fissure 
(Dalrymple-Slellwag's  sign)  on  increased  opening  tension  of  the  eye  (L. 
Bruns)  is  dependent  on  an  abnormal  tonus  of  the  oculomotor  nerve  and 
is,  therefore,  according  to  Eppinger  and  Hess,  to  be  regarded  as  a  sign  of 
autonomous  irritation. 

The  exophthalmus  may  also  be  unilateral.  A  confusion  with  unilateral 
affection  of  the  sympathetic  may  be  avoided  by  attention  to  the  width  of 
the  pupils;  the  latter  should  show  no  differences  in  Basedow's  disease; 
Roasenda  has  described  three  Basedow's  cases  with  unilateral  eye  symptoms, 
and  in  one  of  these  cases  this  symptom  always  remained  limited  to  the  one 
side.  The  unilateral  exophthalmus  sometimes  accompanies  unilateral  en- 
largement of  the  thyroid  gland,  either  with  homolateral  or  with  contra- 
lateral enlargement.  Worms  and  Hamant  have  issued  a  compilation  of  such 
cases. 

V.  Grdfe's  symptoms,  i.e.,  the  failure  of  the  upper  lid  to  follow,  or  only 
retarded  following  of  the  upper  lid  when  the  vision  is  turned  slowly  down- 
ward, the  white  sclera  thus  becoming  visible  at  the  upper  border  of  the 
cornea,  depends  on  an  increased  tonus  of  the  levator  palpebras  muscle. 
V.  Stellwag's  symptom  consists  in  a  rarity  and  an  incompleteness  of  the  in- 
voluntary blinking.  Whereas  in  the  normal  individual  the  blinking  move- 
ment occurs  three  to  five  times  in  the  minute,  in  Basedow's  disease  it  may 
not  occur  for  minutes. 

The  eye  symptoms  are  very  hard  to  reproduce  experimentally,  a  fact 
that  for  a  long  time  stood  in  the  way  of  the  hypothesis  that  Basedow's  dis- 
ease was  a  hyperthyrosis ;  however,  Kraus  and  Friedental  and  Honicke  were 
finally  successful,  through  the  administration  of  very  large  amounts  of  thy- 
roidin  in  inducing  a  widening  of  the  palpebral  fissures  and  an  exophthalmus, 
although  not  to  a  very  marked  degree.  Recently  through  the  use  of  material 
obtained  by  the  removal  of  struma  at  operation  on  human  beings  it  was 
possible  to  induce  typical  exophthalmus  in  a  dog  (Lampe,  Liesegang,  and 
Klose,  and  Bariich).  Worthy  of  mention  here  is  also  the  case  of  Nothaft, 
in  which  an  evident  protrusion  developed  after  an  excessive  use  of  thyroid- 
gland  tablets. 

Finally,  Mdbius's  symptom  consists  in  a  weakness  of  convergence;  by 
fixation  of  the  finger  held  near-by,  the  eye  deviates  without  diplopia ;  perhaps 
this  not  common  symptom  is  to  be  explained  by  a  fatty  degeneration  of  the 


64  THE    DISEASES    OF    THE    THYROID    GLAND 

eye-muscles  which  is  observed  in  severe  cases  of  Basedow's  disease.  Also 
pareses  and  paralyses  of  the  eye-muscles  have  been  observed.  Kappis 
describes  a  case  in  which  the  beginning  of  the  illness  occurred  eleven  years 
previously;  with  gradual  increase  in  all  symptoms  there  developed  an  exten- 
sive paralysis  of  the  eye-muscles  and  other  cranial  nerves.  Kappis  has 
collected  forty  cases  of  eye-muscle  paralysis  in  morbus  Basedowi. 

Sometimes  there  occurs  in  Basedow's  disease  an  excess  of  tears  (Berger) ; 
sometimes,  however,  an  abnormal  dryness  of  the  eye.  In  high-grade  pro- 
trusion the  cornea  may  ulcerate  and  erode,  the  lens  may  fall  out,  and  the 
panophthalmia  that  develops  may  lead  to  death.  Patients  with  Basedow's 
disease  bear  cataract  operation  badly  (MobiHs).  In  rare  cases  there  is 
observed  atrophy  of  the  optic  nerves  (also  obtained  experimentally  through 
administration  of  thyroid  gland,  Birch-Hirschfeld  and  Xonmhuo  Ynvuye) ; 
finally,  mydriasis  sometimes  occurs  on  instillation  of  adrenalin  (O.  Lowi). 
The  adrenalin  mydriasis  is  also  found  in  experimental  hyperthyroidism 
(Eppi)iger,  Falta,  and  Rudinger). 

The  eye  symptoms  belong  to  the  classic  form  of  the  disease.  In  the 
formes  frustes  they  may  be  absent  or  only  suggested.  In  the  following 
briefly  sketched  case  they  were  wanting  altogether: 

Observation  III. — S.  Schm,  fifty-six  years,  shoemaker.  For  about  thirty  years  diffuse 
enlargement  of  the  thyroid,  circumference  of  the  neck  42  cm.  Until  six  months  ago, 
perfectly  healthy.  Then  occurred  gradual  increase  in  the  size  of  the  neck  to  43  cm.  and 
then  to  44  cm.  Lassitude,  sweatings,  difficulty  in  breathing.  His  physician  ordered  for 
him  an  iodine  cure,  which  rapidly  made  matters  worse.  Severe  dyspnea,  cardiac  pal- 
pitations, marked  tremor,  profuse  sweats,  and  profuse  watery  diarrheas,  the  bowels 
moving  ten  to  twelve  times  daily,  loss  of  weight  about  18  kg. 

Markedly  emaciated,  skin  moist,  e3^e  symptoms  not  present.  Both  lobes  of  the 
thyroid  very  much  enlarged,  the  left  somewhat  larger,  pulsation,  vascular  murmurs 
weak.  Perithyroidal  lymph-glands  palpable.  Cardiac  shadows  widened  to  13  cm.  as 
seen  on  X-ray  examination,  shadow  of  the  aorta  increased  to  6  cm.,  tachj^cardia  (i  10-130), 
leucocytes  8500.  of  which  only  T,2>-i  P^r  cent,  are  neutrophiles.  Slight  tremor,  sweats 
(Fig.  8). 

Of  the  alterations  in  the  respiratory  organs  should  be  mentioned  first 
Boundlessness  of  the  voice  {Trousseau),  sensation  of  scratching  in  the  throat, 
and  tormenting,  irritating  cough  (Nothajfft).  The  irritating  cough  was  first 
described  by  Pierre  Marie;  he  found  it  in  twelve  of  fifteen  cases.  This 
symptom  may  be  very  tormenting  and  may  start  in  as  an  early  symptom. 
It  is  accompanied  by  little  or  no  expectoration.  Murray,  however,  observed 
some  cases  in  which  there  existed  a  profuse  expectoration,  a  veritable  bron- 
chorrhea,  which  he  brings  into  analogy  with  the  profuse  watery  diarrheas 
of  the  patients  (paroxysmal  condition  of  excitement  of  the  autonomous 
nerves).  Further  we  should  mention  the  increase  in  the  frequency  of  res- 
piration, the  superficial  breathing,  and  the  air  hunger,  symptoms  which 
occur  paroxysmally  even  as  early  symptoms,  but  which  often  last  for  a  long 
time.     These  symptoms  are  closely  allied  with  the  increased  need  for  oxy- 


Basedow's  disease  65 

gen,  that  is,  with  the  need  for  rapid  loss  of  heat  on  account  of  the  increased 
heat  production.  Bryson's  sign — the  patients  are  not  able  to  expand  the 
chest  in  the  normal  manner  on  deep  inspiration  of  the  thorax — has  nothing 
to  do  with  this,  but  depends  apparently  on  a  weakened  condition  of  the 
respiratory  muscles  as  a  result  of  the  fatty  degeneration  that  was  found  by 
Askanazy  in  all  the  bodily  musculature.  The  acceleration  and  becoming 
shallower  of  the  respiration  was  also  produced  experimentally  hy  Fenyvessy 
by  the  feeding  of  the  thyroid  gland  substance  to  dogs.  It  was  absent  after 
cutting  of  the  vagus  nerves.     The  graphic  registration  of  this  breathing 


Fig.  8. — Absence  of  the  eye  symptoms  in  Basedow's  disease. 

in  Basedow's  disease  shows  very  clearly  the  shallowing  of  the  respiratory 
efforts  and  the  periodic  cessation  of  respiration  (increased  tonus  of  the  vagus, 
Hofbauer).  Eppinger  and  Hess  have  observed  these  respiratory  curves,  es- 
pecially in  those  Basedow  patients  who  showed  signs  of  increased  tonus  in 
other  autonomous  nerves. 

To  the  nervous  symptoms  belong  almost  all  the  symptoms  of  Basedow's, 
as  they  are  for  the  most  part  the  expression  of  the  condition  of  irritation 
of  the  vegetative  nervous  system.  Of  the  nervous  symptoms  in  the  narrower 
sense  is  especially  to  be  mentioned  the  tremor  of  the  separated  fingers,  which 
was  first  observed  in  1862  by  Charcot  and  was  later  described  by  Marie  in  a 
monograph  as  the  principal  and  initial  symptom  of  Basedow's  disease. 
Nothnagel  has  especially  pointed  out  that  the  tremor  is  very  fine.  The 
observations  of  A .  Kocher  give  an  idea  as  to  the  frequency  [of  occurrence]  of 
s 


66  THE    DISEASES    OF    THE    THYROID    GLAND 

the  tremor.  Kocher  found  it  clearly  manifested  in  sixty  cases  out  of  sixty- 
three.  Slight  psychic  emotions  can  make  the  tremor  more  evident.  In- 
tended movements  do  not  ordinarily  increase  it.  Fine  coordinated  move- 
ments may,  however,  be  disturbed  or  made  impossible  on  account  of  strong 
tremor.  Very  strong  tremor  may  also  assume  a  choreic  character.  In 
fully  developed  cases  the  patients  are  often  in  an  "etat  de  vibration  per- 
petuelle."  The  tremor  may  also  affect  the  tongue,  eyelids,  lips,  the  lower 
extremities,  diaphragm,  and  respiratory  muscles;  the  number  of  vibrations 
reaching  about  8  to  9.5  in  the  second,  as  many  as  in  progressive  paralysis  and 
alcoholism;  while  in  senile  tremor  and  paralysis  agitans  the  number  is  less. 
The  tremor  may  be  readily  reproduced  experimentally  by  the  feeding  of 
thyroid  gland. 

An  exactly  similar  tremor  is  seen  sometimes  transitorily  in  hysteria  and 
neurasthenia,  as  the  graphic  registration  has  shown. 

A  further  symptom  is  muscular  weakness,  even  paraparesis  of  the  legs 
has  been  observed  (giving  away  of  the  legs).  Stern  regards  this  as  hysterical. 
Also  transitory  monoplegias  and  hemiplegias  have  been  observed.  Not 
rarely  occur  drawing  pains  in  the  entire  body,  or  only  in  the  arms  or  legs, 
or  in  the  shoulders,  and  especially  in  the  neck.  Kocher  found  them  in  a 
great  number  of  his  cases.  Mbhius  does  not  believe  that  they  are  in  direct 
connection  with  hyperthyrosis.  That  there  is,  however,  such  a  connection 
is  made  certain  by  the  investigations  of  Falta,  Xewburgh,  and  Nobel,  who 
obtained  the  pains  in  numerous  cases  after  the  administration  of  thyroid 
gland  substance.  The  same  is  also  true  of  the  headache  which  is  very 
common  in  Basedow's  disease;  indeed  it  may  be  the  initial  symptom  and  is 
very  common  in  artificial  thyroidism.  Also  the  insomnia  of  the  Basedow 
patient  may  occur  as  the  initial  symptom;  in  many  cases  it  occurs  for 
weeks,  varying  [in  intensity],  and  may  reduce  the  patient  very  much. 

Almost  always  occur  alterations  in  the  mental  life,  abnormal  irritability, 
unmotivated  gaiety,  hasty  speech,  rapid  flow  of  thoughts,  an  indication  of 
flight  of  ideas,  rapid  change  of  mood,  terrifying  dreams;  the  character  alters^ 
the  patient  becomes  mistrustful,  choleric,  capricious,  strikingly  euphoric,  or 
often  very  much  depressed.  Mbbius  happily  compares  this  condition  with  a 
very  slight  "Rausch"  in  which  a  maniacal  mood  may  readily  occur,  and  in 
which  a  conversion  into  depression  may  readily  follow.  Attacks  of  laughing 
and  crying  may  occur,  and  combination  with  hysteria  is  not  rare.  Some- 
times the  condition  terminates  in  delirium,  confusion  with  hallucination,  and 
coma. 

The  transition  of  these  mental  alterations  into  a  true  psychosis  is  not 
rare.  Often  it  is  the  maniacal  conditions,  often  the  depressions,  that  pre- 
vail. Also  the  picture  of  melancholia  may  develop.  According  to  Saltier, 
out  of  one  hundred  and  fifty  cases  in  literature,  more  than  seventy  belong 
to  manic-depressive  insanity.     For  the  comprehension  of  these  alterations  in 


Basedow's  disease  67 

the  psychic  life  the  observation  is  important  that  in  individual  cases  similar 
conditions  may  occur  after  the  administration  of  thyroid-gland  tablets. 
Conditions  of  excitement  are  not  uncommon  in  thyroidism.  Cases  of 
thyroidin  intoxication  insanity  have  also  been  observed  (Boinet,  Parhan  and 
Marbe).  The  authors  last  mentioned  observed  two  cases,  in  whom  after  the 
ingestion  of  great  amounts  of  tablets  there  set  in  complete  confusion  and 
hallucination.  The  manifestations  disappeared  with  the  withdrawal  of  the 
administration  of  thyroid.  The  following  case  {Falta,  Newburgh,  and 
Nobel)  is  instructive : 

Observation  IV. — Woman,  aged  fifty,  who  for  a  half  a  year  had  suffered  loss  of  weight, 
headaches,  insomnia,  associated  with  psychic  depression  and  thoughts  of  suicide.  There 
was  also  present  glycosuria.  The  condition  gradually  ameliorated  and  after  some  weeks' 
stay  at  the  clinic  the  patient  felt  very  well.  Then  the  patient  took  thyroid  tablets  for 
three  days,  upon  which  the  psychic  depression  and  thoughts  of  suicide  recurred.  On 
the  withdrawal  of  the  drug  these  disappeared. 

Already  Brunei  mentioned  that  Basedow's  disease  is  not  associated  with 
any  special  psychosis;  when  a  true  psychosis  occurs  in  it,  we  may  well  assume 
that  a  psychopathic  predisposition  already  existed  and  that  the  hyper- 
thyrosis  constituted  the  determining  factor. 

Of  the  symptoms  aifecting  the  digestive  tract  we  shall  mention  first  in- 
creased flow  of  saliva.  This  symptom  often  occurs  paroxysmally,  and  even 
initially;  more  rarely  there  is  a  dryness  of  the  mouth.  When  the  flow  of 
saliva  is  increased,  there  is  an  increased  tonus  of  the  nerves  of  the  salivary 
glands;  when  the  flow  is  diminished  there  is  an  increased  tonus  of  the  sympa- 
thetic nerves  of  the  salivary  glands  (formation  of  a  thickly  flowing  secretion) 
or  irritation  of  the  sympathetic  nerves  of  the  salivary  glands  (Eckhardt) ; 
also  the  noticeably  increased  diuresis  may  exercise  an  influence  here.  The 
sHght  degree  of  acidity  of  the  gastric  juice,  that  is  usually  observed  in  rare 
cases  of  Basedow's  disease  {Eppinger  and  Hess),  points  also  toward  an  in- 
creased gastric  tonus.  Sometimes  crises  of  hyperacidity  are  observed 
(Maranon) .  Ordinarily,  however,  subacidity  is  present  (Wolpe) .  Especiafly 
important  symptoms  are  vomiting  and  diarrhea  {Pierre  Marie) ,  because  they 
greatly  reduce  the  patient.  Vomiting  is  found,  according  to  Saltier,  in  15 
per  cent,  of  all  cases.  Ordinarily  it  occurs  paroxysmally,  for  the  most 
part  without  any  relation  to  ingestion  of  food,  often  without  any  nausea. 
When  there  has  been  no  ingestion  of  food  it  is  usuafly  thin;  the  paroxysm 
may  last  for  a  whole  day,  in  which  case  the  vomiting  may  occur  thirty  times 
during  the  day  and  be  uncontrollable.  For  the  most  part  it  is  unaft'ected 
by  medication;  it  may  disappear  as  rapidly  as  it  came,  and  may  be  followed 
by  a  period  of  increased  ingestion  of  food.  More  common  are  the  profuse 
watery  diarrheas  (according  to  Saltier  in  30  per  cent,  of  all  cases).  For  the 
most  part  they  are  painless.  Twenty  to  thirty  stools  a  day  may  occur. 
They  may  lead  to  scaphoidal  retraction  of  the  abdomen  as  in  cholera  (Fr.  v. 


68  THE    DISEASES    OF    THE    THYROID    GLAND 

Midler).  The  diarrheas  are  hardly  influenced  by  medication.  In  rarer 
cases,  admixture  with  blood  may  be  observed.  Vomiting  and  diarrhea 
may  also  be  produced  in  animal  experimentation  by  feeding  with  or  injec- 
tion of  thyroid  gland  substance.  In  human  beings,  administration  of  thyroid 
gland  tablets  continued  over  only  a  short  period  may  suffice  to  produce 
action  on  the  bowels.  In  two  cases,  Falta,  Xewburgh,  and  Xobel  observed 
that  on  the  third  day  of  the  thyroid  medication  the  previously  solid  stools, 
that  occurred  only  once  a  day,  had  now  become  soft  and  failed  to  show 
the  impressions  of  the  haustra,  and  that  on  the  third  day  two  soft  stools 
occurred.  On  withdrawal  of  the  medication,  the  stools  again  showed  their 
former  consistency.  Kocher  observed  one  case  with  obstinate  constipation, 
in  which  simultaneously  with  the  appearances  of  the  rather  acute  develop- 
ment of  Basedow's,  diarrheas  developed.  The  statement  of  Kocher,  that 
in  none  of  the  sixty-three  cases  of  Basedow's  described  by  him  did  consti- 
pation exist,  dare  not  be  generalized.  I  have  seen  several  cases  of  formes 
frustes  with  constipation  (see  Observation  V).  Mbhiiis  regards  the  profuse 
diarrhea  of  morbus  Basedowi  as  the  expression  of  the  effort  to  cast  out  the 
thyroid  gland  substance  that  is  circulating  in  excess.  From  this  standpoint 
it  would  not  be  uninteresting  to  test  the  stools  as  to  their  iodine  contents.  It 
is  safe  indeed  to  assume  a  marked  increase  in  the  secretion  in  the  intestines. 
This  and  the  paroxysmal  occurrence  confirms  the  assumption  of  Mobius. 
In  the  higher  degrees,  there  is,  in  addition,  apparently  slight  inflamma- 
tory swelling  of  the  intestinal  mucous  membrane;  at  least  we  may  observe 
this  in  experiments  on  animals  in  which,  in  the  highest  degrees  of  thyroid- 
ism,  hemorrhages  into  the  mucous  membrane  may  occur.  We  may  assume 
also  an  increased  secretion  of  the  pancreatic  juice,  in  accordance  with  the 
experiments  of  Balint  and  Molndr;  these  authors  found  in  the  watery  evacu- 
ations an  abnormal  quantity  of  tryptic  and  diastatic  ferment.  Whether  we 
may  regard  the  profuse  diarrheas  as  an  expression  of  vagotony,  as  Eppinger 
and  Hess  believe,  appears  to  me  questionable,  for  vagotony  is  inclined  to 
be  associated  with  spastic  obstipation. 

We  should  sharply  distinguish  from  these  profuse  diarrheas  the  dis- 
turbances of  fat  absorption  that  are  sometimes  found  in  morbus  Basedowi. 
Adolph  Schmidt  and  H.  Salomon  have  described  one  case  apiece.  I  have 
added  seven  cases,  in  which,  as  in  Salomon's  case,  the  fat-splitting  was 
relatively  good,  so  that  the  disturbances  lay  especially  in  the  absorption. 
In  the  case  very  carefully  investigated  by  me  the  dry  substance  contained  53 
per  cent,  fat,  of  which  24.7  per  cent,  was  neutral  fat,  44.2  per  cent,  soaps, 
and  3 1. 1  per  cent,  fatty  acids.  Sometimes  the  fat  stools  are  found  only 
on  the  overloading  of  the  intestines  with  fat  {v.  Noorden).  Of  late  BittorJ 
has  contributed  a  pertinent  case.     I  here  report  two  others: 

Observation  V. — Ad.  K,  thirty-three  years,  locomotive  stoker,  entered  the  first  medical 
clinic  December,  191 1.     Xo  hcreditarj-  taint,  was  always  well  until  Xovcmber,   1905. 


Basedow's  disease  69 

Then  struck  by  a  locomotive,  fell  on  the  left  side,  for  three  weeks  hematuria  and  fever.  At 
the  beginning  also  unconsciousness,  then  severe  headache,  vertigo,  nausea.  Imme- 
diately after  the  accident  began  tremors,  palpitation,  anxiety,  insomnia,  and  twitchings 
in  the  lower  extremities.  Eight  days  after  the  accident,  the  patient  noticed  an  enlarge- 
ment of  the  right  lobe  of  the  thjToid  gland.  Soon  afterward  marked  pulsating  in  the 
vessels  of  the  neck  and  oppressive  feeling  of  heat,  and  burning  of  the  skin  of  the  throat 
and  neck.  This  condition  continued  from  this  time  on  without  essential  alteration. 
The  patient  states  that  he  has  become  pee\'ish  and  irritable  and  afraid  of  people.  His 
muscular  strength  has  diminished,  he  tires  easily,  and  often  has  drawing  pains,  also 
headaches,  vertigo,  and  sometimes  vomiting,  also  very  hea\y  sweats.  Ordinarily  sHght 
constipation,  from  time  to  time  a  period  in  which  three  or  four  broth-hke  evacuations  of  a 
gray  color  occur  daily. 

Rather  thin;  the  face  especially,  but  also  the  skin  of  the  throat  and  upper  part  of 
the  breast  a  burning  red.  On  disrobing  and  on  excitement  the  redness  increases.  Pro- 
nounced dermographism.  On  stroking  the  skin  with  the  handle  of  the  percussion 
hammer  there  are  elicited  streaks  the  breadth  of  which  is  that  of  a  finger. 

The  right  lobe  of  the  thyroid  is  enlarged,  about  the  size  of  an  apple.  Surface  smooth, 
elastic,  but  not  hard  in  consistence,  e"\ddent  pulsation,  vascular  murmurs.  In  the  neigh- 
borhood, enlarged  lymph-glands.  Points  of  exit  of  the  trigeminal  nerves  tender  to 
pressure.  Slight  paralysis  of  the  sjinpathetic  on  the  right.  All  eye  symptoms  negative. 
To  Rontgen  examination  slight  widening  of  the  shadow  of  the  aorta  to  6  cm.,  and  of 
the  heart  to  12 3^  cm.     Pulse  120-140. 

Blood  pressure,  according  to  Riva-Rocci,  taken  on  the  arm  140.  On  the  left  middle 
finger  {Gartner)  ^^. 

Later  measurements: 
Riva-Rocci,  130-120; 
Gartner,  70. 
After  two  weeks: 
Riva-Rocci,  120-110; 
Gartner,  55. 

Blood:  Erythrocytes.   5.000.000. 
Leucocytes  9200.  of  which: 
Polynuclear  neutrophiles,  55  per  cent. 
Lymphocytes.  :3,2  per  cent. 
Large  mononuclears.  14  per  cent. 
EosinophUes,  i  per  cent. 

Several  later  blood  examinations  gave  similar  results. 
Alimentary  glycosuria  fioo  gm.  dextrose")  4.24  gm.  of  sugar. 

The  stools  frequently  show  the  luster  of  fat  and  a  gray  color.  After  250  gm.  of  oat- 
meal and  300  gm.  butter,  tj-pical  fat  stools.  The  microscopical  examination  shows  little 
neutral  fat,  but  manj'  soap  balls  and  fat  needles. 

Profuse  sweats,  in  which  the  bedclothes  are  soaked  through.  On  the  soles  of  the 
feet  exist  pea-  to  bean-sized  vesicles  filled  with  serous  fluid,  which  burst,  and  leave  the 
cutis  exposed. 

Marked  tremor  of  the  hands,  intensified  on  movements. 
Examination  of  the  fundamental  exchange  {Dr.  Bernstein). 

CO-  O2  RQ  Per  kilogram  body  weight 


237.6  289.0  0.804   I 

220.2  293.0  0.741    \ 

230. I  296.5  o. 776 


CO2  0-2 

o-^S  4-17 


70  THE    DISEASES    OF    THE    THYROID    GLAND 

The  fundamental  exchange  is  therefore  somewhat  increased. 

Result:  Forme  fruste  of  Basedow's  after  trauma  with  all  important  symptoms 
(tachycardia,  sweats,  tremor,  increase  of  the  fundamental  exchange,  mononucleosis) 
with  exception  of  the  eye  symptoms.     In  addition,  fat  stools  and  alimentary  glycosuria. 

Observation  VI. — A.  Schr.,  woman  aged  thirty-three  years.  First  entered  clinic  Jan.  9, 
19 13.  Father  was  very  nervous  and  easily  excited.  Menstruation,  which  began  at  the 
age  of  fourteen  years,  occurs  regularly  every  four  weeks,  lasts  four  to  eight  days,  not 
painful.  Seven  years  ago,  luetic  infection,  after  which  unilateral  headache,  for  one  year 
diplopia.  Two  children,  that  are  very  nervous,  two  miscarriages,  the  one  before  the  in- 
fection, the  other  after  it.     For  three  months  menstruation  very  sparse. 

The  present  illness  began  three  months  ago.  At  first  insomnia  and  severe  headaches, 
then  marked  palpitations.  Dyspnea,  profuse  sweats,  severe  tremors  in  the  hands  and 
feet.  Conditions  of  excitement,  sometimes  vomiting.  During  the  last  three  months  has 
lost  about  10  kg.,  the  throat  is  enlarged,  for  six  weeks  the  eyes  protrude.  During  the  first 
week  five  to  six  stools  daily,  of  normal  consistence,  but  of  a  white- grayish  color. 

Exophthalmus  distinct,  but  not  marked.  Thyroid  enlarged,  diffusely,  distinct 
tremor,  marked  tachycardia. 

Blood-pressure.     Gartner,  95.     Riva-Rocci,  135. 

Leucocytes  5500  (of  which  55  per  cent,  polymorphonuclear  neutrophiles  and  i  per 
cent,  eosinophiles). 

Alimentary  glycosuria  positive  (with  100  gm.  dextrose  0.57  gm.,  with  50  gm.  dextrose 
2.4  per  cent,  with  30  gm.  dextrose,  negative). 

Overloading  with  fat  at  present  does  not  lead  to  fat  stools.     No  diarrhea  now. 

The  cases  with  fat  stools  all  seem  to  show  certain  characteristics.  Al- 
most always  they  are  formes  frustes  with  absent  or  slightly  developed  eye 
symptoms.  In  addition  all  cases  up  to  the  present  have  shown  latent  dis- 
turbances in  the  carbohydrate  metabolism.  In  three  cases,  the  disease 
developed  after  a  trauma.  For  a  close  relationship  between  thyrogenic 
glycosuria  and  fat  stools  speaks  also  the  observation  that  both  disturbances 
retrogress  simultaneously,  either  spontaneously  or  after  therapeutic  pro- 
cedures (exposure  to  Rontgen  rays).  It  is  not  unlikely  that  both  come 
about  through  an  inhibition  of  the  internal  secretory  activity  of  the  pan- 
creas. At  least  there  must  also  be  assumed  a  direct  action  of  the  excessively 
produced  thyroid-gland  secretion  on  the  intestinal  mucous  membrane,  for 
in  diabetes  mellitus  the  absorption  capacity  of  fat  is  perfectly  normal. 
I  do  not  speak  here  of  the  fat  stools  in  cases  of  diabetes  mellitus  with  closure 
of  the  pancreatic  ducts,  as  in  these  it  is  known  that  the  disturbance  in  the 
splitting  of  neutral  fat  is  prominent.  The  observations  of  Balint  and  Molndr, 
that  I  have  already  mentioned,  do  not  speak,  as  these  authors  believe, 
against  my  assumption,  for  they  are  dealing  with  watery  diarrheas  that  have 
nothing  to  do  with  fat  stools  and  that  mostly  occur  in  the  other  forms  of 
Basedow's  disease.  Up  to  the  present  I  have  seen  only  one  case  with  fat 
stools  in  which  formerly  profuse  diarrheas  had  existed. 

The  examination  of  the  blood  in  Basedow's  disease  usually  gives  normal 
figures  for  the  red  blood  cells  and  the  hemoglobin.  In  cases  where  a  diminu- 
tion is  present,    the   iron-content   is,   according   to    the  investigations   of 


Basedow's  disease  71 

Rossin  and  Jellinek,  very  much  reduced.  The  coagulation  capacity  of  the 
blood  is  in  the  most  cases  delayed.  Kottmann  and  A .  Lidsky  found  in  thirty- 
seven  cases  this  delay  in  78.3  per  cent.,  a  normal  coagulation  time  in  5.4  per 
cent.,  and  an  acceleration  in  16.2  per  cent.  In  the  cases  in  which  it  was  de- 
layed, it  approximated  normal  figures  after  operation.  The  delay  also  exists 
in  experimental  hyperthyroidism  {Kostlivy).  These  facts  explain  why  in 
operations  on  Basedow's  patient  the  control  of  hemorrhage  is  often  difficult. 
According  to  Kottmann  the  serum  of  Basedow's  patients  works  in  a  retarding 
way  on  autolysis;  also  the  freezing-point  lies  lower  than  under  normal  con- 
ditions. Fr.  Kraus  and Friedenthal  found  that  the  blood-serum  of  Basedow's 
patients  acts  in  a  mydriatic  manner.  A.  Frdnkel  found  an  increased  action 
on  the  wave-motions  of  the  rabbit-uterus  after  the  death  of  the  animal. 
These  findings  do  not  point  absolutely  to  an  existing  adrenalinemia  {0^ Connor, 
Falta,  Fleming).  Therefore  the  far-reaching  conclusions  that  Kostlivy 
has  drawn  from  these  findings,  as  to  the  sympathcotonizing  components 
of  the  secretion  of  the  thyroid  gland,  are  purely  hypothetical.  Of  greater 
importance  is  the  alteration  in  the  leucocyte  formula  first  described  by 
Th.  Kocher.  There  exists  at  first  a  slight  leucopenia  and  almost  regularly, 
even  in  the  early  stages,  mononucleosis.  The  statements  of  Kocher  have 
been  confirmed  by  numerous  investigations  {Caro,  Ciuffini,  Gordon  and 
V.  Jagic,  Roth,  Buhler,  Kappis,  van  Lier,  Kostlivy,  Turin  and  others).  The 
mononucleosis  is  also  found  in  the  formes  frustes;  but  it  is  also  common 
in  struma  without  Basedow's  symptoms  (Milller,  Ch.  Kappis,  van  Lier, 
and  others).  Cases  of  Basedow's  with  absent  mononucleosis  seems  to  belong 
to  the  great  exceptions  {Kostlivy,  Roth,  Borchardt,  the  author). 

Observation  VII. — C.  A.,  twenty-one  years  old,  student.  For  about  six  weeks  rapid 
enlargement  of  the  thyroid  gland.  Former  circumference  of  the  throat  39  cm.,  now  42 
cm.  Tachycardia,  labile  pulse,  sweats,  tremor,  stools  formerly  sluggish,  sluggish  also  at 
present.  Diffuse  enlargement  of  the  thyroid  gland,  consistence  weak,  pulsation  of  the 
carotid.  No  eye  symptoms.  Apex-beat  broadened  and  increased.  In  the  urine  traces 
of  sugar,  after  overloading  (2  rolls,  four  pieces  of  sugar),  2  per  cent. 

Blood  examination: 

Leucocytes,  7000  of  which: 

Neutrophiles,  68.6  per  cent. 

Lymphocytes,  25.3  per  cent. 

Mononuclears,  4.6  per  cent. 

Eosinophiles,  1.5  per  cent. 

After  several  months,  essential  improvement  in  all  manifestations,  high  tolerance  for 
carbohydrates. 

It  seems  to  me,  however,  that  great  caution  is  necessary  in  regarding  the 
blood  picture  in  cases  of  Basedow's  as  normal,  as  the  alterations  of  the 
blood  picture,  like  those  of  the  other  symptoms  of  Basedow's^undergo  great 
changes.     The  following  is  a  case  in  point: 

Observation  VIII. — Fl.  R.,  woman,  thirt3'-iive  years  of  age.     First  came  under  observa- 


72  THE    DISEASES    OF    THE    THYROID    GLAND 

tion  Dec.  12,  1912.  Apparently  no  hereditarj' nervous  predisposition.  ]Menses  first  ap- 
peared in  the  eleventh  year  of  life,  flow  abundant,  regular,  lasts  for  three  daj's  every  four 
weeks.  Five  normal  births.  Three  years  ago  a  miscarriage  at  the  second  month.  Since 
that  time,  development  of  Basedow's  disease.  Since  that  time,  too,  menses  are  accompanied 
with  severe  pain,  especially  backache.  The  flow  is  less  in  amount.  When  the  exophthal- 
mus  first  developed,  her  face  took  on  a  terrified  appearance,  which  her  acquaintances 
observed;  she  felt  very  well  otherwise,  and  the  ophthalmologist  made  the  diagnosis, 
Basedow's  disease.  Only  several  months  afterward  began  to  develop  watery  diarrheas, 
cardiac  palpitations,  dyspnea,  nose-bleeds,  headaches,  rheumatoid  pains  in  the  extremi- 
ties, lassitude,  sensation  of  dizziness,  and  extraordinary  psychic  irritability;  the  condition 
gradually  became  worse,  with  a  transitory  period  of  amelioration  during  the  summer  before 
I  saw  her.  There  occurred  moreover  insomnia,  sweats,  pains  in  the  calves,  pain  in  the 
forehead  and  eyes  on  reading,  also  transitory  marked  flow  of  tears.  The  appetite  very 
changeable,  at  times  voracious  appetite,  then  again  anorexia. 

Distinct  protrusion,  v.  Grdfe^s  symptoms  plainly  positive,  Lowi's  symptom  plainly 
positive.  Tachj'cardia  extremely  variable,  the  pulse  varying  from  80  to  150.  Subjec- 
tively, rather  marked  oppressions;  marked  falling-out  of  hair,  inclination  to  slight  rises 
of  temperature.  Marked  sweats,  very  variable.  Thyroid  gland  diffusely  enlarged 
(right  lobe  somewhat  more  than  the  left),  soft,  plainly  pulsating,  distinct  palpable  thrill, 
over  it  a  diastolic  vascular  murmur. 

Alimentary  glycosuria  (200  gm.  dextrose)  negative. 

Blood-pressure — Riva  Rocci  130,  Gartner  85;  these  differences  were  regularly  found  on 
repeated  examinations. 

At  the  beginning  of  the  observation  the  above  symptoms  were  present,  except  that 
the  tachycardia  was  very  slight  and  the  tremor  of  the  hands  scarcely  demonstrable. 

The  blood  examination  now  shows: 

Leucocytes,  8000  of  which: 

Polymorphonuclear  neutrophiles,  70  per  cent. 

Eosinophiles,  2  per  cent. 

Lymphocytes,  21  per  cent. 

Large  mononuclears,  7  per  cent. 

Later  the  condition  became  worse,  the  pulse  rate  rose  to  about  130,  the  tremor  be- 
came distinct,  the  blood  examination  now  showed  9000  leucocytes,  of  which: 

Polymorphonuclear  neutrophiles,  60  per  cent. 

Eosinophiles,  2  per  cent. 

Lymphocytes,  27  per  cent. 

Large  mononuclears,  11  per  cent. 

Also  the  examination  of  the  respirator}^  exchange  of  gases  gave  indeed  always  an 
essential  increase,  but  appreciable  variations  {Dr.  Bernstein). 


COl- 

02 

CO2  per  kg. 
and  m. 

O2  per  kg. 
and  m. 

RQ 

On  Jan.  12th 

220.5 

280.5 

3-82 

4.86 

0.786 

15th 

213. 1 

270.8 

3.67 

4.67 

0.787 

1 6th 

229.9 

316.9 

3-96 

5-46 

0.725 

19th 

238.6 

2S4.5 

4. II 

4.90 

0.839 

Also  the  examination  of  the  excretion  of  urine  showed  in  the  first  period  0.45  and  0.37 
gm.  U.  (on  the  7th  and  8th  day  of  the  purin  free  diet). 


Basedow's  disease  73' 

In  the  second  period  0.52 — 3rd  day  of  the  purin  free  diet. 

0.78      20  gm.  sodium  nucleinate  (the  greater  part  vomited). 

0-53 

0.75     200  gm.  meat. 

0.6I 

In  this  case  we  find  therefore,  in  spite  of  very  evident  Basedow's  symp- 
toms, the  blood  picture  at  first  normal,  and  then  showing  the  typical 
changes.  I  observed  a  short  time  ago  a  still  more  striking  case.  Here  in 
the  beginning  all  the  typical  signs  of  a  Basedow's  disease  were  present. 
The  tremor  was  especially  strong.  The  blood  examination  showed  8800 
leucocytes  with  65.8  per  cent,  polymorphonuclear  neutrophiles,  2.2  per 
cent,  eosinophiles,  0.5  per  cent,  mast-cells,  5.5  per  cent,  transitionals,  and 
26  per  cent,  lymphocytes.  After  two  weeks  another  blood  examination 
was  made.  This  showed  53  per  cent,  polymorphonuclear  neutrophiles,  7 
per  cent,  eosinophiles,  0.5  per  cent,  mast  cells,  45.5  per  cent,  lymphocytes. 
The  clinical  picture  was  not  essentially  changed  otherwise.  It  is  worthy 
of  mention  that  for  some  days  before  the  second  count  much  meat  had 
been  ingested. 

For  the  interpretation  of  the  blood  alterations  in  Basedow's  disease  it  is 
important  to  note  that  the  mononucleosis  increases  on  the  ingestion  of  thy- 
roid-gland tablets,  while,  as  we  shall  see  later,  it  decreases  in  conditions 
of  athyrosis,  the  blood  picture  approaching  the  normal.  This  relationship 
was  first  described  by  Falta,  Newburgh,  and  Nobel;  and  lately  Th.  Kocher 
apparently  without  knowing  our  work,  has  written  about  the  practical 
significance  of  this  finding. 

Intercurrent  febrile  diseases  bring  about  the  transitory  disappearance  of 
the  mononucleosis  {Roth).  I  have  seen  a  case  of  Basedow's  disease,  in  which 
a  croupous  pneumonia  developed.  Before  the  development  of  the  pneu- 
monia, there  were  6200  leucocytes  with  46  per  cent,  neutrophilic  cells; 
at  the  height  of  the  pneumonia  there  were  17,100  leucocytes  with  87  per 
cent,  neutrophiles.  It  is  also  known  that  a  transitory  neutrophihc  hyper- 
leucocytosis  occurs  in  Basedow's  patients  a  short  time  after  the  removal 
of  the  struma. 

The  mononucleosis  is  readily  produced  experimentally  by  feeding  with 
thyroid-gland  tablets.  Bertelli,  Schweeger,  and  /  have  regarded  it  as  the 
expression  of  an  excitation  of  the  autonomous  system.  Eppinger  and  Hess 
have  explained  in  like  manner  the  hypereosinophilia  sometimes  observed  in 
Basedow's  disease.  We  must  consider  in  this  connection  not  only  the 
absolute  or  often  only  relative  increase  in  the  mononuclear  cells,  but  must 
regard  as  of  value  the  relative  and  always  absolute  diminution  in  the  neutro- 
philic cells  in  the  peripheral  vessels.  In  the  cases  with  leucopenia  the  num- 
ber of  mononuclear  cells  is  not  increased  absolutely,  in  spite  of  the  marked 
relative  increase;  here  the  alteration  of  the  leucocyte  formula  is  brought 
about  exclusively  through  the  marked  deficiency  in  neutrophilic  cells.     In 


y4  THE    DISEASES    OF    THE    THYROID    GLAND 

the  initial  stage,  especially  on  sudden  overdissemination  of  thyroid  glandular 
secretion,  there  may  well  be  chiefly  an  abnormal  distribution  of  the  neutro- 


FiG.  Q.— Diffuse  enlargement  of  the  thyroid  gland  in  Basedow's  disease. 

philes  in  the  vascular  tree,  leading  to  the  above-mentioned  leucocytic  for- 
mula ;  for  after  feeding  with  thyroid  substance  to  dogs  we  found  in  the  cap- 
illarv  blood  of  the  Hvers  of  these  dogs  hyperleucocytosis  with  marked  pre- 


Basedow's  disease  75 

dominance  of  the  neutrophilic  cells.  Later  there  occurs  a  permanent  altera- 
tion of  the  hematopoietic  apparatus,  consisting  in  a  hyperplasia  of  the 
lymphatic  apparatus.  With  this  alteration  stand  in  harmony  the  swelling 
of  the  lymph-glands  so  often  observed  in  Basedow's  disease  {Gowers),  espe- 
cially the  swelling  of  the  perithyroidal  lymph-glands  {Fr.  Miiller,  Passler, 
Kocher,  and  others),  and  also  the  perivascular  round-cell  infiltration  of  the 
typical  Basedow  struma,  the  hyperplasia  of  the  rest  of  the  lymphatic  appa- 
ratus {Fr.  Muller  and  others),  the  tonsils,  lingual  papillae,  intestinal  follicles, 
the  hyperplasia  of  the  spleen  and  the  thymus  gland  (Bonnet,  Gierke,  Thor- 
becke,  V.  Hansemann,  Rossle,  Hart).  In  severe  acute  cases,  a  distinct  splenic 
tumor  can  appear  as  an  early  symptom.  Schlesinger,  a  short  time  ago, 
reported  such  a  case.  Of  late  great  practical  significance  has  been  ascribed 
to  the  h>'perplasia  of  the  thymus.  According  to  Capelle's  statistics,  44  per 
cent,  of  the  cases  of  Basedow's  disease  that  died  of  intercurrent  diseases 
showed  a  hyperplasia  of  the  thymus,  82  per  cent,  of  the  cases  that  died  of 
Basedow's  disease  itself,  and  almost  100  per  cent,  of  the  Basedow's  cases 
that  died  on  operation.  In  these  cases  it  is  questionable  whether  the  thy- 
mus hyperplasia  is  responsible  for  the  death.  Perhaps  death  was  due  more 
to  the  status  lymphaticus,  perhaps  more  to  the  failure  of  the  chromaftin 
organs.  I  shall  defer  the  consideration  of  the  thymogenic  Basedow's  disease 
until  the  discussion  of  the  theory. 

Of  the  metabolic  disturbances  should  be  mentioned  first  of  all  the  ema- 
ciation, which  is  so  important  practically.  A.  Kocher  found  this  in  88  per 
cent,  of  the  cases  among  his  very  large  number.  It  is  present  in  the  fully 
developed  form.  It  may  set  in  very  early  and  progress  in  a  uniform 
manner;  in  other  cases  it  may  increase  in  acute  exacerbations  that  may 
frequently  be  repeated  (crises  d'  amaigrissement,  Huchard).  Almost  regu- 
larly such  periods  of  increased  emaciation  are  associated  with  the  increase 
of  other  Basedow's  symptoms.  In  the  fully  developed  forms  15-20  kilo- 
grams may  be  lost  in  a  few  months.  Even  in  the  incomplete  forms,  a  slight 
grade  of  emaciation  is  absent  relatively  seldom.  In  the  case  of  Basedow's 
in  which  the  emaciation  is  marked,  there  not  infrequently  develops  a  severe 
grade  of  cachexia  (cachexie  thyreoidienne,  Gauthier).  In  other  patients 
there  may  graduaU}^  set  in  a  reversal  of  affairs,  in  which  the  loss  may  be  more 
or  less  rapidly  made  up.  In  rare  cases,  even  obesity  may  develop.  In  the 
great  majority  of  cases  the  appetite  is  increased,  especially  at  the  beginning; 
and  there  is  often  polyphagia.  Of  course,  the  increase  of  appetite  often  re- 
mains behind  the  much  greater  requirements.  Later  the  appetite  often 
becomes  less.  If  vomiting  or  diarrheas  are  superadded,  the  body  weight 
rapidly  falls. 

The  cause  of  emaciation  in  spite  of  the  increased  appetite  depends  in 
part  on  an  increase  of  the  caloric  production  through  the  thyroid  secretion 
produced  in  excess.     Fr.  v.  Midler  first  pointed  out  that  in  spite  of  the  abun- 


76 


THE    DISEASES    OF    THE    THYROID    GLAND 


dant  supply  of  calories,  in  Basedow's  disease  the  body  weight  often  falls. 
The  demonstration,  that  the  fundamental  exchange,  that  is  the  CO2  produc- 
tion and  the  O2  consumption  in  a  fasting  condition  with  the  exclusion  of  all 
muscular  activity,  is  increased  in  Basedow's  disease,  was  first  furnished  by 
Magnus-Levy,  and  later  by  Thiele  and  Nehring,  Stiive,  H.  Salomon  and  others, 
by  means  of  the  Zuntz  apparatus.  Steyrer  investigated  the  increase  of  ex- 
change by  the  Voit-Pettenkofer  respiration  apparatus.  In  the  severer  cases 
the  increase  of  exchange  may  reach  70  per  cent.  I  reproduce  here  Magnus- 
Levy's  instructive  table: 


Age,      .Height, 
years  cm. 


Weight, 
kg. 


O2 


CO2 


O2  Per  cent, 

cc.  per    '    normal 
kg.  values 


1.  Acute,  very  severe  case 

2.  Very  severe  chronic  case 

3.  Severe  chronic  case 

4.  Somewhat  lighter  chronic  case .  . 

5.  Light  case 

6.  Cured  by  operation  ten  years  ago 

7.  Simple  goiter 


20 
26 
22 

55 

20 

about 40 

66 


158 
150 
161 
156 
148 
171 
142 


7 

34«- 

5 

344- 

I 

305- 

9 

266. 

0 

213. 

0 

282. 

5 

176. 

295.0 

236.  2 
256.0 

299 -3 

181. 1 

241 .0 

143  I 


170 
170 

142 

122 

105 

100 

90 


A  very  interesting  example  is  furnished  by  the  following  case  investigated 
by  Dr.  Bernstein. 

Observation  IX. — H.  J.,  twenty-two  years  old,  pronounced  true  infantilism.  Two 
years  ago  and  one  year  ago  tetany,  simultaneously  with  aggravation  of  a  stomach  affec- 
tion that  had  lasted  a  long  time.  With  the  decline  of  the  second  period  of  tetany  pro- 
nounced manifestations  of  hyperthyrosis.  After  a  gastroenterostomy  there  was  no 
recurrence  of  the  tetany.  The  Basedow's  manifestations  (tachycardia,  sweats,  tremors) 
remained,  or  improved  only  a  little.  Eye  symptoms  were  entirely  absent.  The  in- 
vestigations of  the  fundamental  exchange  gave 
CO2  O2  RQ 


Per  kilogram  of  body  weight 
CO2  O2 


182.2 


185.6 


229. 1 

0.796 

227.4 

0.793 

222.  I 

0.836 

4-45 


5-6i 


In  other  cases  Salomon  could  show  that  the  caloric  production  is  also 
present  in  the  formes  frustes.  The  case  just  detailed  (Observation  IX)  and 
Observation  V  agree  in  that  they  show  that  the  increase  of  the  exchange 
may  also  be  distinct  in  the  formes  frustes  that  pursue  their  course  without 
eye  symptoms. 

Furthermore,  I  would  refer  to  Observation  VIII  where  the  examination  of 
the  gaseous  exchange  showed  that  like  the  rest  of  the  Basedow's  symptoms 
the  caloric  production  is  subject  to  great  variation. 

The  increase  of  fundamental  exchange  may  also  be  demonstrated  ex- 
perimentally through  the  administration  of  thyroid  gland;  it  is,  however,  not 
very  great,  and  in  some  individuals  remains  absent. 

The  question  as  to  which  way  the  influence  of  the  thyroid-gland  secretion 


BASEDOW  S    DISEASE  77 

acts  in  increasing  the  metabolism  has  been  much  discussed.  The  tremor 
alone  is  not  responsible  for  it,  for  after  exclusion  of  the  tremor  by  hyoscine 
the  exchange  is  not  essentially  reduced  (Magnus -Levy).  This  author  be- 
lieves in  a  raising  of  the  exchange  in  the  resting  cells.  Andersson  a,nd Berg- 
man have  contradicted  this,  as  after  large  doses  of  iodothyrin  and  thyroidin 
they  found  no  increase  after  complete  relaxation  of  the  muscles  and  during 
sleep.  These  experiments  however  do  not  show  very  much,  because,  as 
previously  mentioned,  many  normal  individuals  behave  refractorily  to  the 
administration  of  thyroid  gland.  To  my  mind,  we  should  not  leave  uncon- 
sidered in  the  explanation  of  the  increase  of  the  fundamental  exchange  the 
violent  increase  of  tonus  of  the  whole  vegetative  nervous  system  and  the 
heightened  activity  of  the  organs  affected  by  it.  The  increase  of  the  caloric 
production  cannot  alone  constitute  the  cause  of  the  emaciation,  but  there 
must  be  added  to  it  a  disturbance  in  the  regulatory  mechanism  that  governs 
the  taking  up  of  nutrition.  Here  come  into  consideration  especially  the 
disturbances  of  the  stomach  and  intestines.  I  refer  to  what  I  have  said  on 
this  subject  in  the  first  chapter. 

In  Basedow's  disease  also  the  protein  exchange  is  increased,  that  is,  the 
individuals  affected  need  more  protein  or  more  oxygen-free  energy  especially 
in  the  form  of  protein-sparing  carbohydrates  to  maintain  themselves  in 
nitrogen  equilibrium.  In  the  accounting  of  the  equilibrium  we  must  con- 
sider also  the  N-loss  on  account  of  profuse  sweats.  Hirschlaf  estimates  it 
as  2-4  gm.  in  twenty-four  hours.  As  is  the  case  with  all  the  other  Basedow's 
symptoms,  the  increase  of  the  protein  exchange  may  show  great  variations. 

The  increase  of  the  protein  exchange  is  shown  very  prettily  in  the  ex- 
periments of  Rudinger.  In  a  nearly  N-free  diet,  rich  in  carbohydrates  and 
fats  (according  to  Lander  green),  in  normal  human  beings,  the  nitrogen  in  the 
urine  falls  rapidly  to  4-5  gm.  a  day.  In  Basedow's  patients,  Rudinger  found 
7-8  gm.  N.  on  the  fourth  day.  The  increase  of  the  protein  exchange  may 
also  be  demonstrated  experimentally  by  the  feeding  with  thyroid-gland  sub- 
stance. Bleihtreu  and  Wendelstadt  saw  after  administration  of  thyroid-gland 
tablets  in  human  beings  a  negative  N-equilibrium  that  could  be  raised 
by  the  addition  of  butter  and  sugar.  Since  the  time  of  Bleihtreu  and 
Wendelstadt' s  experiments,  many  investigations  have  been  carried  out 
that  show  the  raise  in  the  protein  exchange  through  thyroid  medication 
[Mayerle) .  In  an  experiment  of  Matthes  there  was  shown  after  strumectomy, 
with  the  patient  on  the  same  diet,  an  improvement  of  a  previously  negative 
N-equilibrium.  On  the  administration  of  dried  goiter,  the  excretion  of  ni- 
trogen rose  again.  Also  in  animal  experimentation  could  be  demonstrated  a 
rise  of  the  protein  exchange  {Fritz  Voit).  This  was  shown  plainest  in  in- 
vestigation of  the  metabolism  during  fasting  {Eppinger,Falta,  and  Rudinger). 

The  question  whether  in  hyperthyroidism  the  increase  of  the  protein 
exchange  is  primary  or  only  the  result  of  an  increased  carbohydrate  and  fat 


yS  THE    DISEASES    OF    THE    THYROID    GLAND 

exchange  is  mostly  answered  that  the  increase  of  the  protein  of  exchange 
is  primary.  Fritz  Voit  found  in  dogs  after  feeding  with  thyroid-gland  sub- 
stance a  negative  nitrogen  equilibrium  even  when  the  diet  contained  abun- 
dant fat,  so  that  fat  could  even  be  deposited  [in  the  body].  This  experiment 
does  not  seem  conclusive  as  the  nitrogen-free  energy  in  the  diet  was  exclu- 
sively upheld  by  fat.  The  same  objection  may  however  be  made  against  the 
statement  of  Magnus-Levy  that  on  the  administration  of  fat  or  on  abundant 
fat  deposition,  the  loss  of  nitrogen  is  indeed  appreciably  restricted,  but  not 
entirely  done  away  with.  In  the  experiment  of  Rudinger  the  elimination 
of  nitrogen  could  be  depressed  to  the  Lander  green's  minimal  quantity,  if 
larger  quantities  of  nitrogen-free  energy  (with  abundant  carbohydrates) 
were  ingested  for  a  long  time.  We  can  therefore  conclude  that  in  hyper- 
thyroidism there  exists  only  a  heightening  of  the  physiological  relations. 
This  is  indeed  true  for  the  lighter  grades,  but  in  the  higher  grades  the  de- 
generative changes  of  the  muscular  substances  such  as  are  described  by 
Askanzy,  speak  for  a  toxic  disturbance. 

Jaquet  and  Svenson  state  that  in  the  Basedow's  patients  the  exchange 
after  ingestion  of  food  is  raised  higher  than  in  normal  individuals.  In  the 
investigations  of  Forges  and  Fribram  the  fundamental  exchange  after  transi- 
tory copious  administration  of  protein  was  found  to  be  abnormally  high.  It 
therefore  seems  as  though  the  metabolism  of  Basedow's  patients  were  espe- 
cially labile,  the  administration  of  protein  perhaps  increasing  the  activity 
of  the  thyroid  gland  in  an  especial  manner.  For  this  perhaps  speaks  also 
the  fact  that  we  can  make  the  thyroid  of  dogs  extremely  poor  in  iodine  by 
abundant  administration  of  meat,  this  pointing  to  a  rapidly  leading  off  of 
the  specific  secretion;  also,  as  is  known,  the  Basedow  struma  is  characterized 
by  its  very  slight  iodine  contents. 

The  disturbances  of  carbohydrate  metabolism  in  Basedow's  disease  do  not 
seem  to  be  of  a  uniform  nature.  There  exists  a  combination  of  hyper- 
thyroidism with  true  diabetes  {v.  Noorden,  Ewald,  Grawitz,  Hannemann, 
Bettmann,  Falta,  and  others).  This  diabetes  shows  only  a  slight  dependence 
on  the  course  of  the  hyperthyroidism.  In  the  cases  I  described,  X-ray  irra- 
diation had  only  a  slight  influence  on  the  elimination  of  the  sugar.  With  this 
agrees  the  fact  that  in  true  diabetes  mellitus  we  can  influence  the  sugar 
elimination  by  administration  of  thyroid  gland  only  in  the  aglycosuric  con- 
dition or  on  light  glycosuria,  while  in  the  higher  grades  of  glycosuria  the 
influence  is  not  so  prominent.  Also  in  the  dog  after  complete  extirpation 
of  the  pancreas,  under  the  administration  of  thyroid-gland  tablets  there  was 
no  appreciable  increase  of  the  D:N  quotient.  In  my  cases  of  diabetes  and 
Basedow's  there  were  profuse  diarrheas,  while  cases  of  true  thyrogenic 
glycosuria,  of  which  I  shall  speak  presently,  show  disturbances  of  fat  ab- 
sorption following  overloading  with  fat. 

The  combination  of  Basedow's  with  true  diabetes  is  not  so  verv  rare. 


Basedow's  disease  79 

Sattler  has  collected  forty  cases  from  the  literature.  In  twenty-six  cases  the 
Basedow's  disease  was  present  before  the  diabetes,  in  eight  cases  the  dis- 
eases appeared  about  the  same  time,  in  the  rest  the  Basedow's  occurred  in 
the  course  of  the  diabetes. 

In  many  individuals  the  hyperthyroidism  determines  a  predisposition 
for  glycosuria.  The  disturbance  may  be  occult,  that  is,  glycosuria  appears 
only  on  the  administration  of  large  amounts  of  pure  grape-sugar.  The  ali- 
mentary glycosuria  in  Basedow's  disease  was  first  described  by  Kraus  and 
Ludwig,  and  by  Chvostek.  It  seems  to  have  its  complete  experimental  corre- 
late in  the  alimentary  glycosuria  which  may  be  ehcited  on  the  abundant  ad- 
ministration of  thyroid-gland  tablets  in  many  normal  individuals  and  in 
animal  experiment  {Ewald,  J.  Dale,  Dennig,  v.  Noorden,  Bettmann,  Georgjew- 
sky,  Strauss,  and  others) .  The  disturbance  in  the  carbohydrate  metaboHsm 
may,  however,  also  be  manifest,  that  is  glycosuria  is  found  on  mixed  diet. 
Such  cases  of  spontaneous  glycosuria  do  not  appear  to  be  common  (Lewin, 
V.  Nothaft,  A.  Kocher,  Falta).  Also  Observation  VII,  reported  previously, 
belongs  to  this  group.  The  glycosuria  is  characterized  as  thyro genie  by  the 
fact  that  it  comes  on  with  the  development  of  Basedow's  disease,  and  disappears 
again  with  its  amelioration,  and  that  after  the  cure  of  the  Basedow's  also  the 
overloading  tests  show  entirely  normal  relations.  It  is  to  be  distinguished 
from  the  alimentary  glycosuria  of  Basedow's  in  degree  only,  as  the  alimentary 
glycosurias  also  disappear  on  the  spontaneous  or  therapeutically  induced 
improvement  of  the  Basedow's.  This  is  observed  especially  after  X-ray 
irradiation  of  the  thyroid  {Schwarz,  Hirschl,  Falta).  The  thyrogenic  gly- 
cosuria seems  chiefly  to  occur  in  traumatic  Basedow's,  and,  as  had  been 
mentioned  previously,  is  frequently  combined  with  disturbances  of  fat 
absorption. 

In  the  combination  of  Basedow's  with  true  diabetes  there  may  well  be 
assumed,  in  addition  to  the  disease  of  the  thyroid  gland,  an  independent 
lesion  of  the  insular  apparatus  of  the  pancreas.  On  the  other  hand  I  would 
regard  that  in  the  true  thyrogenic  glycosuria  the  hyperthyroidism  brings 
with  it  a  marked  additional  loading  of  the  internal  secretory  activity  of 
the  pancreas,  with  the  implication  that  the  internal  secretory  activity  of  the 
pancreas  is  weakened,  whether  by  the  thyroid  secretion  or  by  other  factors 
is  not  known.  If,  however,  the  pancreas  is  not  equal  to  the  necessary  breadth 
of  function,  especially  if  an  alimentary  overloading  is  added,  glycosuria  makes 
its  appearance.  This  hypothesis  seems  to  be  explained  in  an  unforced 
manner:  i.  by  the  fact  that  hyperthyroidism  does  not  lead  to  glycosuria  in 
all  individuals;  2.  that  the  glycosuria  disappears  with  the  retrogression  of 
the  hyperthyroidism,  and  that  after  this  retrogression  ahmentary  overload- 
ing does  not  lead  to  glycosuria.  Distinction  of  the  pancreatogenic  from  the 
thyrogenic  glycosuria  is  not  attended  with  any  difficulty;  but  there  are,  how- 


8o  THE    DISEASES    OF    THE    THYROID    GLAND 

ever,  transitions,  that  is  to  say  those  cases  in  which  the  glycosuria  occurs 
under  the  use  of  thyroidin  medication  {Fried.  MiiUer).  In  such  cases,  just 
as  in  the  case  of  Ewald  (myxedema  in  which  diabetes  developed  on  the 
continued  use  of  thyroidin  medication  and  persisted  after  its  withdrawal) 
there  might  very  well  be  supposed  also  a  disease  of  the  insular  apparatus, 
which  up  to  the  time  had  been  latent,  and  which  had  been  made  manifest 
through  the  thyroidin  medication. 

For  the  understanding  of  many  of  the  characteristics  of  the  metabolism 
in  Basedow's  patients  we  must  note  that  the  action  of  thyroidin  depends 
on  the  constitution  of  the  affected  individual.  As  was  mentioned  previously, 
in  normal  individuals  the  action  of  thyroidin  on  the  gas  exchange,  the  protein 
and  the  carbohydrate  metabolism  is  often  intensive,  while  other  indi- 
viduals are  entirely  refractory  to  the  same  dose  of  thyroidin.  The  consti- 
tutional differences  probably  lie  in  the  different  degrees  of  excitability  of 
the  vegetative  nervous  system,  and  this  has  perhaps  its  deeper  foundation 
in  the  different  reaction  capability  of  the  ductless  glandular  system.  Now 
it  seems  that  in  Basedow's  patients  alterations  of  constitution  occur  in 
the  course  of  the  disease.  So,  for  example,  v.  Wagner  mentions  a  case  of 
Basedow's  disease,  in  which  the  initial  rapid  emaciation  was  followed  by  the 
development  of  an  obesity,  that  had  the  characteristics  of  an  essential  obesity. 
Not  so  very  rarely,  too,  are  observed  cases  of  Basedow's  disease  in  which  the 
initial  rapid  emaciation  changes  to  a  condition  in  which  the  patients  not  only 
recover  what  they  have  lost,  but  when  placed  on  a  little  superfluous  diet, 
they  become  fat  in  spite  of  the  fact  that  they  may  still  show  symptoms  of 
hyperthyroidism.  Magnus-Levy  reports  a  case  of  Basedow's  that  after 
subjective  and  objective  amelioration  received  daily  for  four  and  one-half 
weeks  two  or  three  thyroidin  tablets,  without  there  occurring  an  aggrava- 
tion of  the  Basedow's  symptoms  or  an  increase  of  the  exchange  of  gases. 
A  similar  case  was  observed  by  the  author.  It  was  that  of  a  forme  fruste 
with  distinct  Basedow's  symptoms  (without  eye  symptoms)  and  glycosuria. 
After  X-ray  irradiation  of  the  thyroid  gland  all  symptoms  disappeared; 
and  high  tolerance  for  carbohydrates  soon  came  on.  When  the  patient 
again  presented  himself  after  several  months,  thyroidin  medication  for 
three  days  (nine  tablets  a  day)  could  be  administered  without  an  appear- 
ance of  increase  of  the  pulse  rate  or  of  alimentary  glycosuria. 

The  thyroid-gland  secretion"  has  an  enormous  influence  on  the  salt  met- 
abolism. As  W.  Scholz  first  pointed  out,  it  increases  the  elimination  of  phos- 
phorus, especially  through  the  intestine.  The  increase  [of  the  phosphorus] 
in  the  feces  may  reach  as  much  as  25  per  cent.  -Older  observations  of  v. 
Noorden  and  the  later  ones  of  Oeri  have  shown  that  the  distribution  of 
phosphorus  to  the  kidney  and  intestine  is  exclusively  dependent  on  the  elimi- 
nation of  calcium ;  of  calcium  only  a  very  shght  part  is  to  be  found  in  the  urine, 
by  far  the  greater  part  is  to  be  found  in  the  feces.     When  the  calcium  elimi- 


BASEDOW  S    DISEASE  61 

nation  increases,  a  part  of  the  phosphorus  goes  to  the  intestine  with  the 
calcium.  Investigations  of  Bolaffio,  Tedesco  and  the  author  on  fasting  dogs 
show  that  under  the  influence  of  thyroidin  the  X  :  P2O5  quotient  in  the  urine  is 
markedly  increased,  and  that  further,  in  agreement  with  Scholz,  the  elimina- 
tion of  phosphorus  in  the  feces  is  very  much  increased  and  that  the  ab- 
normal distribution  of  phosphorus  to  the  kidneys  and  intestine  is  called 
forth  by  an  increase  of  the  calcium  elimination  by  way  of  the  intestine. 

It  should  be  mentioned  further  that  in  Basedow's  disease  Forschhach 
found  strikingly  slight  amounts  of  creatinin  in  the  urine.  Also  the  ex- 
ogenous factor  (addition  of  meat  extract)  seems  to  be  very  small.  In  many 
a  case  of  Basedow's  disease  there  exists  in  addition  a  pronounced  polyuria, 
that  cannot  be  explained  alone  by  the  greater  gram  molecular  amount 
[Molenmenge]  of  the  urine  on  account  of  the  increased  metabolism.  Here 
there  is  well  present  an  excitation  of  the  nerves  of  the  renal  vessels. 

Later  investigations,  not  as  yet  published,  by  Zehner  and  me  as  to  the 
uric  acid  metaboHsm  in  Basedow's  disease  have  led  to  a  very  remarkable 
result.  We  found  in  all  the  severe  cases  thus  far  investigated  by  us  not  only 
that  the  endogenous  factor  of  the  U-elimination  was  strikingly  small,  but 
that  also  the  exogenous  U-elimination  was  quite  unusually  small.  I  have 
reported  such  an  investigation  in  Observation  VIII,  and  would  express  the 
opinion  that  a  portion  of  the  uric  acid  is  further  decomposed  under  the 
influence  of  the  hyperthyroidism. 

There  are  found  not  rarely  in  Basedow's  disease  ephemeral  increases  in 
temperature.  These  were  first  described  by  Bertoye.  Already  Charcot  had 
mentioned  in  opposition  to  Bertoye  that  they  were  very  much  less  frequent 
than  Bertoye  stated.  Among  his  numerous  cases,  they  were  never  seen  by 
Kocher.  They  have  been  seen  however  by  Sattler.  At  all  events,  it  is  cer- 
tain that  in  many  cases  of  Basedow's  disease  the  equilibrium  of  heat  is  very 
labile,  and  that  on  slight  provocations  the  regulation  is  broken  through  in 
the  sense  of  a  hyperthemia.  Frederick  Muller  saw  regularly  in  one  case 
marked  rises  of  temperature  after  the  administration  of  quinine.  Eppinger 
and  Hess  saw  them  in  cases  after  the  injection  of  atropine.  Moreover  cases 
of  peracute  Basedow's  disease  are  described  that  previous  to  death  showed 
marked  tachycardia  with  delirium,  and  a  simultaneous  rise  of  temperature 
to  4o-4i°C.  (Friedr.  Muller).  Also  Hirschlaf  saw  in  a  case  a  terminal 
rise  of  temperature  to  40°.  I  have  often  seen  in  severe  cases  of  Basedow's 
disease  transitory  rises  of  temperature  to  39°,  without  finding  a  ground  for 
them  in  the  examination.  After  goiter  operations,  as  is  known,  there  have 
been  observed  marked  rises  of  temperature  that  last  for  several  days  {Ber- 
gert,  Reinbach,  Kocher,  Lanz).  Riedel  found  them  also  after  the  operation 
for  ordinary  goiter,  although  those  which  occur  after  operations  for 
exophthalmic  goiter  are  essentially  higher.  Kostlrvy  found  in  all  cases  after 
operation  pronounced  neutrophilic  hyperleucocytoses,  but  postoperative 
6 


82  THE    DISEASES    OF    THE    THYROID    GLAND 

h}'perthermia  only  in  cases  with  thyrotoxic  symptoms  or  in  true  Basedow's. 
Kocher,  Lanz,  v.  Bnins,  and  ScJniltze  explain  this  hyperthermia  as  an  absorp- 
tion fever,  as  in  operations  on  the  throat  there  are  present  especially  favor- 
able conditions  for  the  formation  of  hematomata.  ^More  probable  is  the 
explanation  that  in  consequence  of  the  manipulation  of  the  gland  more  thy- 
roid secretion  is  absorbed  and  perhaps  also  the  cervical  sympathetic  is  irri- 
tated mechanically.  The  objection  of  Schultze  that  the  injection  of  extracts 
from  such  strumas  calls  forth  no  essential  rises  of  temperature  in  other  people 
does  not  seem  to  me  tenable,  as  normal  individuals  do  not  possess  the  lability 
of  thermal  equilibrium  that  exists  in  the  Basedow's  patients. 

The  skin  in  Basedow's  disease  is  usually  delicate,  pliable,  moist,  readily 
reddened,  showing  well  a  lively  play  of  the  vasomotors.  Increased  sweat 
secretion  is  almost  constant  and  is  mostly  present  from  the  beginning  of  the 
disease.  As  is  the  case  with  all  the  s\Tnptoms  of  Basedow's  disease,  the 
sweats  undergo  great  variations;  sometimes  they  occur  only  at  night,  and 
often  they  are  influenced  greatly  by  psychic  excitations.  In  rare  cases,  the 
sweats  have  an  odor  {v.  Basedow's,  Danscher.  Observation  V,  previously  re- 
ported). ]Many  of  the  patients  sweat  more  on  one  side.  In  consequence  of 
the  abnormal  moisture  of  the  skin  due  to  the  sweats  there  is  found  in  most 
Basedow's  patients  a  reduction  of  the  resistance  to  the  passage  of  an  electrical 
current;  this  was  first  described  by  F.  Chvostek  and  Vigouroux  and  was  more 
exactly  studied  by  O.  Kahler.  On  account  of  the  marked  excretion  of  sweat, 
miliaria  sometimes  occur;  the  formation  of  larger  vesicles  with  elevation 
of  the  epidermis,  as  in  Case  K.  (Observation  V),  seems  to  be  a  very  rare 
occurrence. 

Pigmentations  are  found  in  about  half  of  all  cases,  and  indeed  on  the  eye- 
lids, lips,  throat,  on  the  Unes  of  constriction  of  the  corset  laces,  on  the 
nipples,  in  the  axillae,  on  the  linea  alba,  exceptionally  on  the  mucous  mem- 
branes, and  also  on  the  genitalia.  In  rare  cases  is  found  a  diffuse  brown 
coloration  of  the  skin  of  the  extremities,  indeed  even  a  bronzing.  In  many 
cases  occur  edematous  swellings,  especially  of  the  eye-lids,  but  also  on  the 
extremities;  they  are  firm  and  do  not  pit  on  pressure.  They  probabh'  differ 
in  nature.  Trophedemas  are  apparently  not  very  rare  in  Basedow's  disease. 
In  many  cases  it  seems  as  though  we  were  dealing  with  a  kind  of  lipodystrophy, 
as  for  example  in  the  case  reported  by  v.  Sc/irdttcr,  in  which  simultaneously 
with  the  emaciation  of  the  upper  half  of  the  body  there  developed  a  con- 
siderable sweUing  of  the  lower  half  of  the  body,  looking  just  like  myxedema. 
Microscopical  examination  showed  a  lipomatosis  with  extraordinary  large 
fat  lobules.  In  this  case  there  was  found  also  a  quite  extraordinary  pigmen- 
tation of  the  skin  in  the  form  of  sharply  circumscribed  surfaces.  I  shall 
refer  later,  in  the  discussion  of  the  pathogenesis,  to  the  myxedematous  swell- 
ings in  this  disease.  There  may  be  found  also  in  certain  cases  hemorrhages 
into  the  skin  and  the  mucous  membranes.     A  common  symptom  in  Base- 


Basedow's  disease  83 

dow's  disease  is  the  falling  out  of  the  hair,  that  sometimes  may  lead  almost 
to  baldness.     Also  the  nails  are  sometimes  fissured. 

Alterations  of  the  osseous  system  occur  mostly  if  the  Basedow's  disease 
has  developed  in  an  individual  who  is  youthful.  Holmgren  has  pointed  out 
that  youthful  Basedow's  patients  show  an  accelerated  growth  in  height  and 
a  somewhat  premature  closure  of  the  epiphysial  junctures.  Very  instructive 
is  a  case  of  Schkarine  in  a  four  and  one-half-year-old  girl  who  showed  an 
abnormally  rapid  growth.  Also  Ballet  reports  a  nineteen-year-old  girl  with 
Basedow's  disease  and  "gigantism."  The  skeleton  of  the  patient  with  Base- 
dow's is  mostly  slender;  the  end  phalanges  are  mostly  pointed  (Revilliod). 
V.  Jaksch  and  Rotky  describe  in  a  case  of  Basedow's  painful  distentions  at 
the  distal  ends  of  the  forearm  bones,  and  later  also  of  the  ribs,  shoulder- 
blades,  upper-arm,  thighs,  etc.  Later  the  case  developed  kyphoscohosis  and 
paraplegia.  The  simultaneous  occurrence  of  Basedow's  and  rheumatoid 
arthritis  has  been  frequently  described  {Jones  and  others) . 

The  alterations  in  the  genitalia  are  mostly  more  pronounced  in  men,  and 
in  severe  cases  there  may  sometimes  be  decrease  of  libido  and  impotence. 
In  women  there  are  usually  alterations  of  menstruation — sometimes  cessa- 
tion of  menstruation  is  an  early  symptom.  On  longer  duration  of  the  disease 
there  may  come  about  an  atrophy  of  the  entire  genital  apparatus  {Cheadle, 
Askanazy,  et  al.).  In  the  case  of  Kleinwdchter  there  occurred,  in  addition  to 
a  pronounced  atrophy  of  the  external  and  internal  genitalia,  even  an  atrophy 
of  the  mammae.  The  relation  between  the  genital  sphere  and  the  thyroid 
gland  is  found  also  in  the  fact,  known  for  so  long,  that  there  is  an  increase  of 
the  volume  of  the  thyroid  at  the  time  of  puberty  and  during  pregnancy. 
There  may  also  occur  during  the  period  of  pregnancy  a  development  of  a 
goiter  {Lawson  Tail),  which  disappears  after  labor  and  recurs  during  the  next 
pregnancy.  Vermorel  refers  the  tachycardia  and  the  cardiac  palpitations 
that  sometimes  occur  at  the  time  of  puberty  to  a  light  grade  of  hyperthy- 
roidism. At  any  rate  it  is  noteworthy  from  this  point  of  view  that  Base- 
dow's disease  is  not  at  all  rare.  During  pregnancy  the  Basedow's  symptoms 
mostly  become  exaggerated  {CJiolmogorof  and  others).  As  the  tendency  to 
Basedow's  disease  is  sometimes  inherited  and  as  in  the  decline  of  Basedow's 
patient  frequently  other  diseases — neuroses  of  the  vegetative  nervous 
diseases,  diabetes,  etc. — occur,  matrimony  is  to  be  advised  against  to 
Basedow's  patients,  or  in  it  conception  is  to  be  avoided  (/.  Novak). 

Basedow's  disease  can  naturally  be  combined  with  many  other  diseases. 
We  should  mention  the  not  rare  combination  with  the  trophoneuroses,  espe- 
cially with  scleroderma.  Such  a  case  was  first  reported  by  Lenhe.  Since 
that  time  numerous  cases  have  been  reported.  An  accurate  compilation  has 
been  made  by  Saltier.  Basedow's  disease  may  be  added  to  an  already  exist- 
ing scleroderma,  or  sclerodermic  symptoms  may  develop  in  the  course  of  a 
Basedow's  disease.     Observers  have  often  found  that  an  improvement  of  the 


84  THE    DISEASES    OF    THE    THYROID    GLAND 

Basedow's  disease  is  associated  with  an  improvement  of  the  scleroderma. 
There  are,  however,  cases  that  take  another  course.  Also  complications  of 
Basedow's  disease  with  tetany  have  often  been  observed  (see  Chapter  IV). 

Pathogenesis. — Before  I  enter  into  the  consideration  of  the  individual 
forms  of  Basedow's  disease,  I  should  like  to  make  a  few  remarks  as  to  the 
theory.  The  observation  of  Fileline  and  of  Dourdoufi  and  Bienfait  that  in 
animals  after  the  transection  of  the  corpora  restiformia  there  occur  tachy- 
cardia, exophthalmus,  and  hyperemia  of  the  thyroid  gland  (unilateral  opera- 
tions are  attended  with  these  phenomena  on  one  side  only),  for  a  long  time 
attracted  many  adherents  to  the  bulbar  theory,  which  attributed  all  the 
Basedow's  symptoms  to  alterations  in  the  brain  stem.  Actually  many 
symptoms  point  to  a  bulbar  origin,  as  for  instance  the  glycosuria  that  some- 
times occurs,  the  alterations  of  the  voice,  and  eventually  the  pareses  of  the 
various  cranial  nerves  {Sattler) .  It  is  indeed  true  that  in  certain  cases  altera- 
tions are  found  in  the  medulla  oblongata  {Mendel  and  others),  but  in  the 
majority  of  cases  these  findings  are  absent.  The  French  school,  especially 
Charcot,  Trousseau  and  Gauthier,  and  in  Germany  Gerhardt  and  Buschan, 
have  regarded  Basedow's  disease  as  a  neurosis,  assuming  that  the  entire 
nervous  system  is  diseased.  Then  Mdbius,  as  has  already  been  mentioned 
in  the  beginning,  placed  the  thyroid  gland  as  the  central  figure  in  the  patho- 
genesis, assumed  a  poisoning  of  the  body  by  the  copious  production  of  a 
harmful  secretion,  and  expressed  the  thought  that  all  forms  of  Basedow's 
disease  (goiters  that  have  become  associated  with  Basedow's  symptoms, 
formes  frustes,  and  the  fully  developed  Basedow's  disease)  all  depend  on  a 
uniform  basis.  Mdbius  first  pointed  out  the  opposition  between  the  symp- 
tom picture  of  Basedow's  disease  and  the  disease  condition  that  ensues 
after  extirpation  of  the  thyroid  gland.  Mdbius's  teaching  gained  ground 
rapidly,  the  predominant  place  of  the  thyroid  gland  in  the  pathogenesis  of 
Basedow's  disease  finding  general  recognition;  but  on  the  contrary  the  views 
as  to  the  kind  of  functional  disturbance  diverged  greatly.  The  view  first 
advocated  by  Notki  and  later  by  Blum,  that  certain  poisons' existing  in  the 
body  were  rendered  nontoxic  {i.e.,  detoxicated)  in  the  thyroid  gland  and  that 
in  Basedow's  disease  this  detoxication  is  incomplete,  may  to-day  be  regarded 
as  untenable.  It  was  displaced  by  the  secretion  theory,  which  maintained 
that  from  the  thyroid  gland  a  specific  active  secretion  is  given  off  to  the 
blood  path  that  is  necessary  for  the  retention  of  certain  body  functions,  or, 
according  to  the  supposition  of  others,  to  the  paralyzing  of  certain  poisons 
circulating  in  the  body.  The  detoxication  theory,  although  in  an  essentially 
modified  form,  again  greets  us  in  the  view  last-mentioned.  In  this  form, 
however,  there  is  as  little  evidence  for  it  as  in  its  older  form.  The  known 
experiment  of  Reid  Hunt,  according  to  which  the  resistances  of  animals  to 
methyl  cyanide  is  somewhat  raised,  is  not  evidence  for  the  detoxication 
theory  as,  as  Reid  Hunt  himself  emphasizes,  the  heightening  of  resistance  can 


Basedow's  disease  85 

be  called  forth  by  the  heightening  of  the  metaboHc  processes  that  ensues  in 
consequence  of  the  administration  of  the  thyroid. 

Oswald,  Minnich,  and  others  assume  that  in  Basedow's  disease  the  thyroid 
furnishes  a  less  active  secretion  (hypothyrosis  or  dysthyrosis) ;  Mobius 
believes,  as  already  mentioned,  in  the  increased  secretion  of  a  substance  that 
is  qualitatively  altered;  while  most  authors,  especially  Fr.  Kraus,  advocate 
the  mere  increase  of  the  thyroid  function  without  qualitative  alteration 
(hyperthyroidism).     For  this  supposition,  which  I  also  advocate,  speaks: 

1.  The  opposition  in  the  symptom  picture  of  Basedow's  disease  and 
myxedema. 

2.  The  fact  that  on  exothyropexy  (conduction  of  the  secretion  of  the 
thyroid  gland  to  the  exterior)  the  thyroid  gland  in  Basedow's  disease  fur- 
nishes more  secretion  than  the  thyroid  of  the  ordinary  strumas. 

3.  The  results  of  surgical  treatment  (diminution  of  the  secreting 
parenchyma) . 

4.  The  aggravation  of  Basedow's  disease  on  the  administration  of 
thyroid  glandular  substances  and  finally, 

5.  Artificial  thyroidism. 

Against  these  points  many  objections  have  been  raised  of  which  I  shall 
mention  only  the  most  important.  Against  point  5  has  been  objected 
that  while  it  is  true  that  most  of  the  symptoms  of  Basedow's  disease  may 
be  produced  on  the  administration  of  thyroid  gland,  they  remain  much  be- 
hind those  of  true  Basedow's  disease  in  intensity,  and  some  of  them,  for 
instance  the  eye  symptoms,  are  not  produced  in  artificial  thyroidism  at  all. 
As  far  as  the  eye  symptoms  are  concerned,  I  must  again  mention  that  Kraus 
and  Friedenthal  observed  exophthalmus  after  the  injection  into  the  blood 
of  rabbits  of  the  thyroid  glandular  juice  contained  in  the  serum,  as  did 
Heinecke  on  long-continued  treatment  with  large  amounts  of  thyroid  glandu- 
lar substance.  In  addition  to-day  exophthalmus  can  be  produced  in  dogs 
on  the  use  of  juice  expressed  from  human  strumas  {Lampe,  Liesegang,  and 
Klose,  Baruch). 

Lampe,  Liesegang,  and  Klose,  on  the  intravenous  injection  into  certain 
breeds  of  dogs  of  fresh  juice  expressed  from  Basedow  strumas,  have  found 
marked  increase  of  the  temperature  and  pulse  rate,  exophthalmus,  glyco- 
suria and  albuminuria.  Death  occurred  in  convulsions.  Expressed  juices 
that  were  obtained  from  normal  thyroid  glands  or  ordinary  strumas  had  no 
effect,  or  very  little  effect.  The  authors  regard  these  experiments  as  evidence 
that  in  Basedow's  disease  there  exists  no  hyperthyroidism  but  a  dysthyroid- 
ism.  The  experiments  are  very  signifi.cant,  but  I  do  not  regard  them  as 
furnishing  evidence  for  a  dysthyroidism.  It  will  not  do  to  leave  altogether 
unconsidered  the  long-known  fact  that,  as  stated  above,  through  the  feed- 
ing with  normal  thyroid  glandular  substances  all  the  symptoms  of  Base- 
dow's can  be  produced  in  a  more  or  less  well-pronounced  manner.     Also 


86  THE    DISEASES    OF    THE    THYROID    GLAXD 

Baruch,  who  experimented  in  a  manner  quite  analogous  to  that  of  Lampe, 
Liesegang.  and  Klose.  and  had  similar  results,  does  not  agree  with  these 
authors'  interpretation. 

]SIuch  cited  is  the  case  of  v.  Xothaft,  which  I  shall  describe  in  detail  on 
account  of  the  interest  that  it  has  attracted.  It  was  that  of  a  forty-tive- 
year-old  man  with  a  corpulency  that  had  been  increasing  for  several  years. 
In  the  course  of  about  five  weeks  he  took  almost  looo  thyroid-gland  tablets. 
In  a  short  time  there  developed  a  complement  of  Basedow's  symptoms  of  which 
I  wall  mention  irritating  cough,  tachycardia,  acceleration  of  respiration, 
slight  increase  of  temperature,  bilateral  exophthalmus.  tremor  of  the  whole 
body,  even  of  the  tongue,  increased  strangury,  glycosuria  (up  to  i  per  cent.), 
morose  mood,  excitement,  and  finally  swelling  of  the  thyroid  gland.  The 
irritating  cough  disappeared  eight  days  after  the  onset  of  the  thyroid 
glandular  therapy,  as  did  also  the  sugar,  without  alteration  of  the  diet;  the 
tremor  disappeared  after  four  weeks;  the  struma,  the  exophthalmus,  and  the 
rest  of  the  eye  signs  lasted  nearly  one-half  year  and  then  retrogressed  almost 
entirely.  Although  here  almost  the  entire  symptom-complex  of  Basedow's 
disease  developed,  the  case  is  however  not  entirely  convincing.  We  shall 
see  later  that  in  many  persons  often  relatively  small  amounts  of  iodine  are 
sufiicient  to  occasion  an  enormous  increase  of  the  function  of  the  thyroid 
gland.  Also  in  the  case  of  v.  Nothafft  the  amounts  of  iodine  contained  in  the 
administered  thyroid  gland  material  may  have  sufficed  for  the  purpose,  as 
speaks  also  the  transitory  development  of  a  struma.  This  objection  might 
very  well  be  raised  to  an  artificial  hyperthyroidism,  unless  the  thyroid  gland 
in  the  aft'ected  individual  were  absent.  Now  in  myxedema  after  thyroid 
operation  we  may  indeed  frequently  observe  an  extraordinarily  high  toler- 
ance for  thyroid-gland  substances,  but  on  the  other  hand,  symptoms  of 
hyperthyroidism  may  be  ehcited  after  the  administration  of  enormous 
amounts.  At  all  events,  we  must  not  forget  that  we  do  not  know  anything 
as  to  the  amount  of  thyroid-gland  secretion  given  oft"  to  the  blood  in  Base- 
dow's disease.  Probably  it  is  very  large.  We  should  further  consider  that 
on  the  peroral  administration  of  large  amounts  the  absorption  would  soon 
suffer  harm. 

Although  I  therefore  do  not  recognize  the  arguments  advanced  up  to  the 
present  time  as  convincing,  I  shall  have  to  acknowledge  that  artificial 
thyroidism  has  not  as  yet  furnished  complete  evidence  for  the  opinion 
here  advocated.  The  greater  intensity  of  the  symptoms  in  true  Basedow's 
always  admits  of  the  possibility  that  hyperthyroidism  is  only  a  partial  phe- 
nomenon of  an  alteration  of  the  central  nervous  system  and  that  the  organism  of 
the  Basedow's  patient  reacts  to  hyperthyroidism  in  a  diferent  manner  than 
the  normal.  The  foundation  for  this  can  perhaps  be  seen  in  a  constitutional 
alteration,  of  which  the  cause  lies  in  the  associated  involvement  and  perhaps 
in  a  functional  increase  of  other  ductless  glands.  The  final  cause  of  all  the 
manifestations  could  well  be  regarded  as  lying  in  the  central  nervous  system. 


BASEDOW  S    DISEASE 


87 


It  has  been  pointed  out  that  the  multiplicity  of  the  Basedow's  symptoms 
cannot  well  be  explained  by  the  functional  increase  of  the  thyroid  gland 
alone,  and  that  therefore  also  on  this  ground  a  qualitative  alteration  of  the 
secretion  must  be  supposed.  This  objection  does  not  hold  in  this  general 
interpretation.  All  the  symptoms  of  Basedow's  disease  may  be  produced, 
at  least  in  miniature,  after  the  administration  of  normal  thyroid  gland. 
What  syndrome  will  develop  all  depends  on  the  constitution  of  the  affected 
individual  {Falta,  Neuhiirgh,  and  Nobel). 

Objections  have  been  raised  to  point  4.  It  is  true  that  in  the  most 
cases  we  observe  under  thyroid  medication  distinct  aggravation  of  the 
Basedow's  symptoms,  such  as  increase  of  the  tachycardia,  arrhythmia, 
sleeplessness,  excitement,  profuse  sweats,  gastrointestinal  disturbances, 
severe  prostration,  etc.  But  there  have  been  reported  cases  in  which 
the  thyroid  medication  acted  favorably.  Quite  complicated  theories  have 
been  advanced  for  the  explanation  of  these  cases;  thus,  for  example,  Mdhius 
believes  that  the  increased  activity  of  the  thyroid  gland  retrogresses  if 
through  the  administration  of  thyroid  glandular  substance  the  gland  is  given 
time  to  recover  itself.  Such  cases  may  be  explained  without  overdrawing 
by  the  observation  that  in  many  cured  cases  of  Basedow's  disease  the 
counter-regulations  develop  strongly.  I  previously  mentioned  a  case  in 
which,  after  the  cure  of  the  Basedow's,  thyroid-gland  tablets  even  in  large 
quantities  would  bring  forth  no  distinct  rehef .  If,  therefore,  thyroid  medica- 
tion takes  place  in  the  declining  stage  of  the  disease,  slight  favorable  results 
may  be  readily  induced. 

The  most  important  point  is  point  i,  the  opposition  in  the  symptom 
picture  of  Basedow's  disease  and  of  myxedema.  I  here  reproduce  the  ex- 
cellent table  of  Kocher: 


Cachexia  Thyreopriva 
Absence  or  atrophy  of  the   thyroid 
gland. 

Slow,  small,  regular  pulse. 

On  application  of  cold  to  the  skin,  all 
vasomotor  changes  are  absent. 

Listless  quiet  gaze  without  expression 
and  animation. 

Narrow  palpebral  fissures. 

Retarded  digestion  and  excretion, 
poor  appetite,  few  demands. 

Slowed  metabolism. 

Thick,  nontransparent,  folded,  dry  to 
scaly  skin. 

Short,  thick  fingers  often  broadened 
at_the  ends. 

Sleepiness  and  tendency  to  sleep. 


Morbus  Basedowi 

Swelling  of  the  thyroid  gland — mostly 
of  a  difl'use  nature,  hyper  vascularization. 

Frequent,  often  tense,  rapid,  now  and 
then  irregular,  pulse. 

Extraordinarily  irritable  vascular  nerv- 
ous system. 

Anxious,  unsteady  gaze  which  is  choleric 
on  fixation. 

Wide  palpebral  fissures,  exophthalmus. 

Abundant  evacuations,  mostly  abnormal 
appetite,  increased  demands. 

Increased  metabolism. 

Thin,  transparent,  finely  injected,  moist 
skin. 

Long,  slender  fingers  with  pointed  end 
phalanges. 

Sleeplessness  and  disturbed  sleep. 


88  THE    DISEASES    OF    THE    THYROID    GLAXD 

Cachexia  Thyreopriva  jMorbus  Basedowi 

Retarded  sensation^  apperception,  and  Accelerated  sensation,  apperception,  and 

action.  action. 

Deficiency  of  thoughts,  listlessness,  and  Flight  of  thoughts,  psychic  excitement 

loss  of  emotivity.  as  far  as  hallucination,  mania  and  melan- 

cholia. 
Awkwardness  and  clumsiness.  Constant  unrest  and  haste. 

Stiffness  of  the  extremities.  Trembling    extremities,    increased    mo- 

bility of  the  joints. 
Remaining  behind  of  bone  growth —  Slender  skeletal   build,    now   and  then 

bones    short    and    thick,    and   often    de-     weak  and  thin  bones. 
formed. 

Constant  feeling  of  cold.  Unbearable  sensation  of  heat. 

Retarded,  heavy,  breathing.  Superficial     breathing     with     deficient 

inspiratory  expansion  of  the  thorax. 
Increase  of  body  weight.  Reduction  of  body  weight. 

Senile    appearance,    even    when    the  Youthful  luxuriant  body  development, 

patients  are  young.  at  least  in  the  initial  stages. 

A.  Kocher  distinguishes,  in  addition  to  these  opposed  symptoms,  symptoms 
that  are  similar  in  both  diseases  and  reckons  under  these  certain  forms  of 
edema,  dryness  and  becoming  gray  of  the  hair,  pigmentations,  and  the 
diminution  of  the  secretion  of  the  sahvary  and  lachrymal  glands  that  is  ob- 
served in  many  cases  of  Basedow's  disease.  One  may  add  to  these  symp- 
toms the  dryness  of  the  skin  seen  in  rare  cases  of  Basedow's  disease  and  the 
glycosuria  of  quite  rare  cases  of  myxedema.  These  "exceptions  to  the 
rule"  will  hardly  suffice  to  limit  essentially  the  opposition  in  the  symptom 
picture  of  the  two  conditions.  For  the  explanation  of  many  of  these  ex- 
ceptions, constitutional  differences  may  be  called  into  account;  for  example, 
they  may  suffice  for  the  explanation  of  the  dryness  of  the  hair  and  of  the 
skin,  and  for  the  diminution  of  the  salivary  secretion.  Eppinger  and  Hess 
regard  the  cause  of  the  opposed  behavior  of  the  sweat  formation  in 
different  cases  of  Basedow's  disease  as  a  different  tonus  of  the  sympathetic 
or  of  the  autonomous  nerves;  surely  such  behavior  does  not  furnish  suf- 
ficient argument  against  the  hypothesis  of  hyperthyrosis,  because  also  in 
artificial  hyperthyroidism  we  saw,  in  certain  cases,  a  diminution  of  the 
sweat  formation  under  the  influence  of  the  thyroid  medication.  As  far 
as  the  behavior  of  the  hair  is  concerned,  in  Basedow's  disease  the  hair  in- 
deed may  be  dry  but  is  also  thin,  while  in  myxedema  it  tends  to  be  thick, 
loose,  and  brittle.  The  explanation  of  other  ''similar"  symptoms  may 
be  attributed  to  the  pathological  correlations;  for  instance,  the  rare 
glycosuria  in  myxedema  may  well  point  to  a  simultaneous  insufficiency  of 
the  pancreas.  I  would  enter  more  fully  only  into  a  discussion  of  one  of  the 
symptoms  detailed,  as  it  is  regarded  by  the  adherents  of  dysthyrosis  as 
an  especially  important  argument.  It  is  the  combination  of  Basedow's 
and   myxedematous   symptoms   in   the   same   patients.     In  Sattkr's   work 


Basedow's  disease  89 

will  be  found  a  compilation  of  such  cases.  The  observation  that  a  fully 
developed  Basedow's  may  gradually  go  over  into  a  myxedema  has  nothing 
striking  about  it,  for  an  overfunctionating  thyroid  may  degenerate  and 
become  functionally  insufficient.  Such  a  case  was  first  described  by  Jojfroy 
and  Achard.  In  a  twenty- three-year-old  woman  there  first  developed  a 
typical  Basedow's  disease,  then  great  weakness,  swelling  of  the  feet,  legs, 
trunk,  the  upper  extremities  and  the  face,  apathy,  great  fatigabihty.  Au- 
topsy showed  a  sarcoma  of  the  pleura  and  disappearance  of  the  thyroid 
parenchyma,  in  the  place  of  which  was  found  connective  tissue.  Confer 
also  the  case  of  Gauthier. 

Concerning  the  cases  with  simultaneous  occurrence  of  Basedow's  disease 
and  myxedema,  I  would  remark  that  in  many  of  these  cases  the  diagnosis 
myxedema  seems  to  me  very  doubtful  indeed.  I  call  to  mind  the  above- 
mentioned  case  oi-V-  Schroiter,  which  microscopical  examination  showed  to  be 
lipomatosis.  Perhaps  something  analogous  is  to  be  seen  in  the  case  of 
Hirschl,  in  which  the  skin  of  the  ankle-joint  was  entirely  normal  and  the 
swelling  of  the  leg  ended  in  a  sharp  ring.  In  this  case,  too,  the  swelling  of 
the  face  was  limited  to  a  pad-like  thickening  on  the  lower  border  of  the 
lower  jar.  The  circumstance  that  the  skin  was  dry  is  no  evidence  for  myx- 
edema; otherwise  there  was  a  typical  Basedow's  disease.  Also  in  both  of 
Loew's  cases — otherwise  typical  cases  of  Basedow's  disease — there  existed 
a  thickening  of  the  extremities  that  involved  the  backs  of  the  feet  little 
if  at  all.     Thyroid  medication  had  no  influence  on  this  thickening. 

It  seems  to  me  further  noteworthy  that  almost  all  the  cases  that  Sattler 
quotes  show  peculiar  complications.  In  two  cases  (cases  of  Mohius  and  of 
Hirschl)  there  existed  at  the  same  time  osteomalacia.  In  the  case  of  S oilier, 
the  myxedematous  swellings  occurred  especially  at  the  time  of  menstruation, 
in  the  case  of  Ulrich  there  were  choreiform  twitchings,  in  the  case  of  Kow- 
aleivsky  epilepsy  since  youth,  in  the  case  of  Holub  there  was  marked  Chvo- 
stek's  sign,  and  in  Osier's  case  there  later  occurred  under  thyroid  medica- 
tion marked  glycosuria.  Moreover,  I  consider  it  possible  that  cases  that 
stand  on  the  border-hne  of  thyroid  glandular  insufficiency  would  under  cer- 
tain conditions  show  lowered  tolerance  for  thyroid-gland  preparations. 
As  example  I  cite  the  following  case: 

Observation  X. — Mrs.  B.,  forty-eight  years,  has  had  five  confinements.  After  the  last 
confinement  there  was  a  gradual  taking  on  of  body  weight,  until  she  weighed  about  125  kg. 
About  twenty  years  ago  she  underwent  a  reduction  cure,  in  the  course  of  which  she  rapidly 
lost  14  kg.  At  the  time,  also,  thyroid-gland  tablets  were  administered.  After  the  treat- 
ment marked  excitability,  cardiac  oppressions,  diarrheas,  sweats,  and  tremor  occurred. 
These  symptoms  lasted  a  long  time.  Then  they  retrogressed  and  the  body  weight  again 
increased.  Three  years  ago  after  inunction  of  an  iodine  salve,  there  was  a  gradual  in- 
crease of  the  Basedow's  symptoms.  The  thyroid  gland  had  formerly  been  large,  and  now 
enlarged  still  more.  Two  years  ago  the  right  lobe  of  the  thyroid  gland  was  extirpated. 
After  the  operation  there  was  gradual  increase  of  body  weight,  about  12  kg.,  sensation  of 


90  THE    DISEASES    OF    THE    THYROID    GLAXD 

cold  (can  scarcely  warm  herself),  skin  dry  and  cold,  mental  sluggishness,  constipation. 
For  several  months  thyroid  medication.  The  skin  again  became  moist,  cardiac  manifesta- 
tions, tachycardia,  and  arrhythmia  again  appeared,  the  patient  was  excited,  the  consti- 
pation disappeared.  Body  weight  decreased.  When  the  thyroid  medication  was  discon- 
tinued, the  weight  increased  again  and  the  myxedematous  symptoms  reappeared.  Since 
that  time,  periods  of  thyroid  administration  were  many  times  introduced,  and  regularly 
after  the  use  of  only  two  to  three  tablets  a  day  for  a  short  time  Basedow's  manifestations 
appeared.  At  present,  after  a  three  weeks'  thyroid  treatment,  there  is  a  slight  tachycardia 
and  especially  marked  arrhythmia.  The  heart  is  dilated,  the  pulse  is  poorly  filled,  the 
skin  is  moist,  there  are  stary  eyes  and  a  very  slight  fine-waved  tremor.. 

Later,  in  the  chapter  on  myxedema,  I  shall  cite  similar  cases.  The 
slight  tolerance  toward  thyroid  preparations  is  in  this  case  certainly  re- 
markable, as  high  tolerance  is  characteristic  for  typical  cases  of  myxedema. 
To  my  mind  there  is  in  this  case  no  necessary  basis  for  the  assumption  of  a 
dysthyrosis.  It  is  well  known  that  a  degenerated  heart  muscle  is  extra- 
ordinarily sensitive  toward  thyroidin.  It  can  very  well  be  conjectured  that 
a  slight  excess  of  thyroidin  would  already  damage  the  heart  muscle,  if  the 
myxedematous  symptoms  have  not  as  yet  altogether  disappeared.  Finally, 
it  remains  to  be  investigated  whether  in  similar  cases  the  myxedematous 
swellings  of  the  skin  are  always  dependent  exclusively  on  the  thyroid  glandu- 
lar insufficiency.  Much  speaks  for  the  fact,  as  above  indicated,  that  in 
such  cases  frequently  also  other  ductless  glands  are  degenerated.  Especially 
frequently  there  occurs  a  simultaneous  affection  of  thyroid  and  hypophysis. 
As  is  known,  there  is  found  an  insufficiency  of  the  pituitary  gland,  alterations 
of  the  skin  and  trophic  disturbances  that  are  similar  to  those  of  myxedema. 
In  many  Basedow's  cases  with  myxedematoid  symptoms,  and  in  cases  of 
myxedema  that  react  to  thyroid  treatment  with  only  partial  improvement 
and  that  may  even  show  signs  of  hyperthyroidism  rapidly,  it  is  quite  prob- 
able that  these  myxedematoid  manifestations  depend  on  a  hypophysial  in- 
sufficiency (see  also  the  chapter  on  the  hypophysis). 

]\Iany  authors  are  disposed  to  ascribe  to  thymus  hyperplasia  an  important 
role  in  the  pathogenesis  of  Basedow's  disease.  Already  v.  Hansemann  was 
of  the  opinion  that  the  cases  of  "thymus  Basedow"  could  be  distinguished 
also  clinically.  Hart  refers  the  cardiac  manifestations  in  Basedow's  disease 
to  the  thymus  hyperplasia  alone  and  sees  in  such  cases  thyroid  hyperplasia 
as  something  secondary.  On  the  other  hand,  Gcbcle  regards  the  enlargement 
of  the  thymus  gland  as  a  compensating  process  that  serves  to  weaken  the 
hyperthyroidism.  Especially  worthy  of  notice  are  the  reports  of  Garre  and  of 
Capelle  and  Bayer,  concerning  the  extirpation  of  the  thymus  gland  in  Base- 
dow's disease.  In  the  case  of  Capelle  and  Bayer,  thymectomy  seemed  to  have 
no  influence  on  the  struma,  the  exophthalmus,  or  the  bulbar  symptoms,  but 
the  cardiac  symptoms  seemed  to  improve.  After  some  weeks  the  mononu- 
cleosis had  disappeared.  Gebelc,  however,  docs  not  regard  the  thymus  in 
this  case  as  enlarged,  and  points  out  that  five  months  after  the  thymectomy 


Basedow's  disease  91 

an  operative  procedure  on  the  thyroid  was  necessary  on  account  of  pro- 
nounced symptoms  of  Basedow's.  According  to  E.  Bircher,  implantation 
into  the  abdominal  cavity  of  dogs  of  thymus  gland  that  came  from  an  indi- 
vidual who  died  from  thymic  death  at  operation  called  forth  temporary 
tachycardia,  conditions  of  excitement,  and  tremor,  and  also  a  struma. 
Present  clinical  and  experimental  contributions  to  this  subject  seem  to 
me  far  inadequate  to  ascribe  to  the  thymus  gland  so  great  a  significance  as 
to  warrant  the  delimitation  of  a  thymogenic  Basedow's. 

Just  a  few  words  as  to  the  place  of  iodine  in  the  physiology  and  pathology 
of  the  thyroid  gland.  Iodine  is  found  in  very  many  organs,  as  in  the  skin, 
the  lungs,  the  ovaries,  the  small  intestines,  the  blood,  the  liver,  the  bile,  the 
hairs,  and  in  the  glandular  part  of  the  hypophysis  {Blum,  B  our  get,  Hejfter, 
Drechsler  and  others).  The  iodine-contents  of  the  thyroid  gland  is,  how- 
ever, much  larger  (according  to  Justus  eight  to  ten  times)  than  that  of  the 
other  organs  relatively  rich  in  iodine.  The  normal  thyroid  gland  of  man 
contains  according  to  Magnus-Levy  about  0.3-0.9  mg.  of  iodine  for  i  kg.  of  dry 
substance.  The  entire  gland  contains  about  2-9  mg.  {Baumann,  Oswald). 
The  thyroid  glands  of  fetuses  and  new-born  children  are  iodine-free.  The 
thyroid  glands  of  herbivora  have  very  high  iodine-contents,  while  the  thyroid 
glands  of  carnivora  have  the  lowest  iodine-contents  {Baumann,  Roos, 
Oswald).  Copious  feeding  of  meats  to  dogs  makes  the  thyroid  gland  very 
poor  in  iodine.  The  activity  of  the  thyroid  glandular  substance  is  bound 
with  its  iodine-contents  and  parallels  these.  As  is  known,  all  the  symptoms 
of  deprivation  after  extirpation  of  the  thyroid  gland  may  be  alleviated  by 
the  administration  of  iodine-containing  thyroid  glandular  substance.  The 
iodine-containing  albuminous  substances  obtained  by  Oswald  from  the 
thyroid  gland,  iodthyroglobulin,  contains  about  1.75  per  cent,  of  iodine. 
The  iodothyrin  obtained  by  Baumann  by  splitting  with  acids  contains  about 
9.3  per  cent.  Oswald  obtained  from  thyroglobulin  by  splitting  with  acid  a 
still  richer  iodothyrin  with  14.29  per  cent,  of  iodine.  While  the  iodthy- 
roglobulin seems  to  possess  the  complete  action  of  dried  thyroid-gland  sub- 
stance, iodothyrin  is  less  active,  even  though  it  possesses  a  greater  height- 
ening power  on  metabolism  and  a  greater  action  on  the  cardiovascular 
apparatus  than  artificially  iodized  albuminous  bodies.  Its  action  is,  how- 
ever, much  less  than  that  of  dried  thyroid  glandular  substance.  While,  for 
example,  we  could  obtain  with  2.7  gm.  of  Bourrougk,  Wellcome,  and  Co.'s 
tablets  distinct  tachycardia  and  other  slight  symptoms  of  thyroidism  in  three 
days,  later  twenty-one  Bayer's  iodothyrin  tablets  daily,  administered  for  a 
long  time,  were  without  effect  (experiment  of  Dr.  Fleming) .  The  iodothyrin 
is  also  incapable  of  alleviating  the  manifestations  of  deprivation  that  occur 
in  youthful  animals  after  thyroidectomy  {Pick  and  Pineles).  Just  as  after 
splitting  with  acids,  the  thyroid-gland  substance,  after  exposure  to  digestive 
ferments,  loses  in  activity.     Exposure  of  short  duration  to  peptic  and  tryp- 


92  THE    DISEASES    OF    THE    THYROID    GLAND 

tic  digestion  does  not  seem  to  alter  the  specific  substances,  as  we  are  able 
to  bring  about  the  complete  action  even  on  peroral  administration.  All 
experiments  point  to  the  fact  that  the  thyroid  gland  carries  iodine  in  a  specifi.c 
organic  combination,  perhaps  iodthyroglobulin. 

The  iodine-contents  of  pathological  glands  varies  greatly.  The  purely 
parenchymatous  Basedow  strumas  contain  almost  no  iodine;  strumas 
rich  in  colloid  are  also  rich  in  iodine.  Investigations  by  Oswald,  A.  Kocher. 
and  others  have  shown  that  the  iodine-contents  of  strumas  rich  in  colloid 
is  really  not  absolutely  greater  than  in  the  normal  thyroid-gland,  but  that 
relatively,  that  is,  taken  in  relation  to  the  amount  of  thyroid-gland  sub- 
stance, it  is  less.  On  the  contrary,  the  holding  in  thyroglobulin  is  abso- 
lutely and  relatively  greater;  in  colloid  goiters  there  is  found,  therefore, 
either  an  iodthyroglobulin  poor  in  iodine  or  less  iodthyroglobulin  and  more 
thyroglobulin.  Probably  in  the  Basedow  struma  the  formed  iodoth^TO- 
globulin  reaches  the  circulation  immediately  in  consequence  of  the  increased 
permeation  with  blood. 

The  function  of  the  thyroid  gland,  if  the  organ  is  altered  pathologically, 
may  be  influenced  by  the  administration  of  inorganic  iodine.  Individuals 
with  normal  thyroid  glands  separate  out  again  the  excess  of  iodine  rather 
promptly,  without  any  disturbance  of  the  iodine  equilibrium.  Strumous 
individuals,  according  to  the  investigations  of  A.  Kocher,  behave  very 
diversely;  in  strumas  with  abundantly  functionating  parenchyma  more 
iodine  is  excreted  than  is  introduced,  so  that  thyroid-gland  tissue  is  melted 
down  and  symptoms  of  thyroidism  may  appear.  In  strumas  with  relatively 
iodine-poor  colloid  this  is  first  iodized;  there  therefore  occurs  an  iodine  re- 
tention, but  on  continued  treatment  with  iodine  there  may  come  about 
melting  down  of  the  colloid  and  thyroidism.  Administration  of  the  phos- 
phates should  favor  the  action  of  iodine  and  keep  back  the  melting  down  of 
tissues.  This  experiment  renders  intelligible  the  old  experience  that  in 
certain  forms  of  struma  the  administration  even  of  very  small  amounts  of 
iodine  leads  to  manifestations  of  thyroidism. 

Koche/s  investigations  stand  in  the  most  intimate  relation  to  the 
older  experience  as  to  the  so-called  iodine  Basedow's.  Coindet,  in  Geneva, 
introduced  iodine  into  therapy  in  1820.  Shortly  afterward  it  was  reported 
by  Coindet  himself  and  by  Gautier,  d'Espine,  Relliet,  and  others  that  after  the 
administration  of  iodine  there  often  occurs  a  series  of  symptoms  that  are 
sharply  distinguished  from  those  of  pure  iodism  (acne,  catarrh  of  the  mucous 
membranes,  etc.).  These  symptoms  (tachycardia,  tremor,  emaciation,  etc.) 
could  develop  in  strumous  individuals  after  the  administration  of  mimimal 
amounts  of  iodine,  and  long  outlast  the  medication.  Already  Lebert  ad- 
vocated the  opinion  that  in  such  cases  the  administration  of  iodine  led  to 
rapid  absorption  of  thyroid  glandular  substance  and  the  symptoms  mentioned 
could  be  referred  to  this.     Brcuer  explained  the  contradiction  that  these 


BASEDOW  S    DISEASE  93 

observations  met  with  in  Paris  by  the  fact  that  only  certain  forms  of  struma, 
as  those  for  example  in  Geneva  or  Vienna,  reacted  to  the  administration  of 
iodine  in  this  manner.  The  regional  difference  in  the  sensitiveness  toward 
iodine  can  be  elicited  from  the  large  series  of  experiments  of  Fleischniann. 
Fleischmann  after  the  administration  of  iodine  to  the  persons  under  inves- 
tigation in  Basel  saw  acceleration  of  the  pulse  in  68  per  cent.,  in  Berne  in  23 
per  cent.,  in  Berlin  in  only  3.7  per  cent.  In  Heidelberg,  the  use  of  iodine 
was  warned  against  by  Krehl.  According  to  the  statement  of  Breuer, 
Kocher,  Mobius,  Ortner,  Goldfiam  (the  last  on  the  injection  of  iodipin  into  a 
person  with  tabes),  there  even  a  typical  morbus  Basedowi  may  develop,  even 
in  cases  in  which  no  struma  existed  before  the  treatment  with  iodine;  or  in 
cases  of  cured  Basedow's  there  may  occur  a  severe  relapse  with  a  new 
enlargement  of  the  thyroid  gland.  Case  B.  (Observation  X),  previously 
reported,  furnishes  a  good  example  of  this;  or  an  existing  Basedow's  dis- 
ease may  be  considerably  aggravated  by  iodine  therapy  (compare  case  S. 
ScJim).  In  Vienna,  according  to  my  observations,  conditions  are  such  that 
one  must  directly  warn  young  persons  with  diffuse  soft  strumas  against  the 
use  of  iodine.  Pineles  has  seen  especially  frequently,  after  the  use  of  iodine, 
the  occurrence  of  the  manifestations  of  thyroidism  in  goitrous  individuals  in 
families  in  which  Basedow's  disease  or  diabetes  has  occurred  or  in  which  a 
neuropathic  disposition  has  existed.  This  was  the  case  even  when  the 
iodine  was  given  in  very  small  quantities. 

It  would  really  be  correct  to  separate  the  cases  of  simple  iodothyroidism 
from  those  of  iodine  Basedow's,  although  there  are  transitions  between  the  two 
groups.  In  the  first  group  of  cases  administration  of  iodine  brings  about  a 
rapid  melting  down  of  thyroid-gland  tissue  and  hence  the  manifestations  of 
thyroidism.  After  the  discontinuation  of  the  iodine  medication  the  mani- 
festations for  the  most  part  rapidly  retrogress,  the  thyroid  gland  remaining 
the  same  in  size  or  becoming  smaller.  In  the  cases  of  iodine  Basedow,  on 
the  contrary,  the  thyroid  gland  increases  in  volume,  and  the  Basedow's 
manifestations  can  long  outlast  the  iodine  medication. 

As  to  the  etiology  of  Basedow's  disease  we  do  not  know  anything  definite. 
The  goiter  noxus  can  play  only  a  subordinate  role,  as  just  the  fully  developed 
forms  of  Basedow's  disease  are  rare  in  goiter  districts.  Neuropathic  pre- 
disposition is  to  be  regarded  at  the  most  as  a  predisposing  factor;  psychic 
and  bodily  traumata  as  well  as  iodine  and  thyroid  glandular  medication  are 
to  be  regarded  as  determining  factors.  Frequently  Basedow's  disease  de- 
velops at  the  close  of  acute  infectious  diseases  (acute  articular  rheuma- 
tism, angina,  typhoid  fever,  scarlet  fever,  etc.).  In  some  cases  an  idio- 
pathic thyroiditis  passes  over  into  it.  Finally,  Kahn  and  myself  in  several 
cases  of  declining  tetany  saw  occurrence  of  thyroid  glandular  swelling  and 
distinct  Basedow's  symptoms.  As  furthermore  the  true  Basedow's  struma 
shows  accumulations  of  lymphocytes  and  as  the  parathyroid  glands  in  such 


94  THE    DISEASES    OF    THE    THYROID    GLAXD 

cases  are  swollen,  many  authors  have  thought  of  an  infectious  etiology  of 
Basedow's  disease.  This  assumption  is  not  however  satisfactory,  as  many 
cases  of  Basedow's  disease  develop  in  complete  health  and  are  entirely  fever- 
free.  Hence  the  acute  infection  is  regarded  by  Mdhius,  de  Qiiervain  and 
others  only  as  the  connecting  link.  As  I  have  already  mentioned,  the 
assumption  of  a  thymogenic  Basedow's  disease  seems  to-day  to  have  but 
little  foundation.  Even  those  who  refer  all  the  symptoms  of  Basedow's 
disease  to  an  increase  of  function  of  the  thyroid  gland  must  recognize  that 
the  cause  proper  of  this  increase  of  function  is  as  yet  unknown.  As  the 
secretion  of  the  thyroid  gland  is  regulated  by  the  central  nervous  system, 
lately  nervous  centers  have  again  been  assumed  (Wiener),  constituting,  in  a 
manner,  a  revival  of  the  bulbar  theory  of  Charcot  and  Geigel  iOppenheim). 
According  to  this  theory  many  of  the  Basedow's  symptoms,  above  all  the 
eye  symptoms  which  are  so  hard  to  produce  by  artificial  thyroidism,  are 
coordinated  with  those  of  the  thyroid  glandular  swelling.  This  theory  would 
at  least  explain  the  rare  observation  that  the  exophthalmus  may  occur 
unilaterally  [Fr.  Miiller,  Roasenda,  Kocher,  and  others). 

The  statements  as  to  the  theory  and  etiology  of  hyperthyrosis  bring  to 
recognition  the  fact  that  the  cause  of  Basedow's  disease  is  not  as  yet  explained. 
Most  of  the  symptoms  can  be  referred  to  the  hyperthyroidism;  the  cause  of  the 
hyperthyroidism  is  possibly  conditioned  centrally,  and  thus  perhaps  a  series 
of  symptoms  and  alterations  in  the  function  of  other  ductless  glands  are  coordinate 
"with  the  hyperthyroidism.  Finally,  we  should  point  out  that  the  not  unusual 
combination  of  the  trophoneuroses  (scleroderma)  with  symptoms  similar 
to  those  of  Basedow's  disease  or  even  typical  hyperthyrosis  obtain  some 
value  in  this  connection  (see  Chapter  I). 

Forms  of  Basedow's  Disease. — In  consequence  of  the  great  variability 
which  Basedow's  disease  presents  in  its  manifestations  and  in  its  course, 
there  has  existed  from  former  years  the  attempt  to  bring  forward  certain. 
symptoms  as  cardinal  symptoms  and  to  lend  to  certain  apparently  more  re- 
mote symptoms  a  greater  nosological  independence.  Originally  the  symptoms 
of  the  so-called  ]Merseburg  triad — exophthalmus,  goiter,  and  tachycardia — 
were  taken  as  the  cardinal  symptoms.  However,  exophthalmus  is  wanting 
in  a  not  inconsiderable  part  of  the  cases  of  this  condition  and,  moreover, 
Pierre  Marie  added  a  new  cardinal  symptom — the  tremor.  The  fact  that  the 
exophthalmus  is  often  permanently  absent  led  Pierre  Marie  to  the  establish- 
ment of  the  formes  frustes,  the  effaced,  or  better,  the  incomplete  forms,  while 
formerly  Charcot  understood  by  forme  fruste  the  residual  condition  after 
improvement  of  the  classic  form.  Gautier  and  Buschan  distinguished  true 
Basedow's  disease  and  the  pseudo-  or  secondary  Basedow's  disease,  regard- 
ing the  former  as  a  general  neurosis  with  the  predominance  of  the  psychic 
and  vasomotor  sphere,  while  the  latter  is  brought  about  by  other  changes 
in  the  organism  among  others  also  a  disturbance  of  function  of  the  thvroid 


Basedow's  disease  95 

gland.  Mohius  distinguished  primary  and  secondary  Basedow's  disease 
according  as  to  whether  the  alteration  of  function  developed  in  a  previously 
normal  or  in  a  goitrously  degenerated  thyroid  gland.  Secondary  Basedow's 
disease  ordinarily  pursues  a  chronic  course  and  is  often  incomplete;  the 
primary  is  often  acute  and  rich  in  symptoms.  The  secondary  form  corre- 
sponds to  the  goitre  basedowifie  {Revilliod  and  Pierre  Marie) .  Mohius  does 
nothowever  ascribe  so  very  great  a  significance  to  this  distinction,  as  he  regards 
the  alteration  of  function  of  the  thyroid  gland  as  the  central  figure.  "The 
cardinal  symptom  is  just  the  tachycardia."  Th.  ivoc/zer  distinguishes  between 
the  fully  developed  forms  and  the  so-called  hyperthyrotoxic  equivalents. 

Fr.  Kraiis  has  separated  out  the  so-called  goiter  heart  as  an  especial 
independent  form.  Apart  from  those  cardiac  disturbances  which  come  about 
through  mechanical  obstruction  to  the  circulation  or  respiration,  there  exists 
additionally  in  goiters,  according  to  Kraus,  a  cardiac  disturbance  associated 
with  other  hyperthyroidal  symptoms,  which  cardiac  disturbance  is  produced 
by  the  thyroidal  secretion  acting  at  a  distance. 

Eppinger  and  Hess  distinguish  between  sympathicotonic  and  vagotonic 
forms,  according  to  whether  the  symptoms  of  excitation  predominate  on  the 
part  of  the  autonomous  or  of  the  sympathetic  nerves.  Characteristic 
for  the  vagotonic  cases  would  be  "a  relatively  sHght  degree  of  tachycardia, 
with,  however,  markedly  pronounced  heart  oppressions,  distinctly  marked 
V.  Grdfe,  and  wide  palpebral  fissures,  absent  Mohius,  shght  protrusion  of 
eyeballs,  the  marked  secretion  of  tears,  outbreaks  of  sweats,  diarrheas,  dis- 
tresses that  are  to  be  referred  to  hyperacidity,  eventually  eosinophiha,  and 
disturbances  of  the  rhythm  and  mechanism  of  respiration,  absent  alimentary 
glycosuria;"  in  the  sympathicotonic  cases,  Eppinger  and  Hess  found  ''marked 
protrusion  of  the  eye-balls,  greatly  increased  cardiac  activity  with  slight  ac- 
centuation of  the  subjective  disturbances,  absence  of  sweats  and  diarrheas, 
marked  falling  out  of  the  hair,  inclination  to  increase  of  fever,  absence  of 
eosinophiha,  no  disturbances  of  respiration,  alimentary  glycosuria." 

The  position  of  many  of  these  symptoms  as  sympathicotonic  or  vagotonic 
is  as  yet  quite  insecure.  Thus,  for  example,  the  interpretation  of  the  sweats 
as  vagotonic  is  not  sufficiently  founded,  because  as  yet  we  have  known  noth- 
ing as  to  the  course  of  autonomous  nerves  of  the  skin.  The  significance  of 
the  individual  phenomena  is  rendered  the  more  difficult  because  there  exist 
both  sympathetic  accelerator  [fordernde]  and  inhibitor  and  autonomous  ac- 
celerator and  inhibitor  fibers.  I  cannot  look  upon  the  alimentary  glycosuria 
as  sympathicotonic,  as  according  to  our  investigations  the  alimentary  factor 
is  to  be  sharply  separated  from  the  nervous  factor,  and  for  the  former  the 
functional  breadth  of  the  pancreas  is  the  determining  factor.  Moreover, 
there  are  undoubtedly  cases,  as  Eppinger  and  Hess  and  recently  v.  Noorden, 
Jr.,  bring  out,  in  the  course  of  which  at  times  the  sympathicotonic,  at  times 
the  autonomotonic,  symptoms  predominate.     Before  everything  else,  how- 


96  THE    DISEASES    OF    THE    THYROU)    GLAXD 

ever,  the  tachycardia  is  evidently  to  be  regarded  as  the  cardinal  symptom 
of  Basedow's  disease;  and,  on  the  other  hand,  the  sweats  or  the  marked  moist- 
ening of  the  skin  is  so  extraordinarily  frequent  that  almost  never  can  we 
speak  of  a  purely  sympathetic  type  in  the  sense  of  Eppinger  and  Hess.  In 
my  opinion  everything  speaks  for  the  fact  that  in  Basedow's  disease  the 
entire  nervous  system  is  in  a  condition  of  overexcitement  and  that  the  pictures 
presented  by  the  vegetative  nervous  system  are  uncommonly  manifold  and 
always  changing. 

Very  recently  Stern  has  entered  the  list  for  the  greater  independence  of 
certain  forms  of  Basedow's  that  he  regards  as  Basedowoid.  In  a  certain 
sense  there  is  in  this  a  reversal  to  the  views  of  Gautier  and  Busclian.  Stern 
divides  the  classic  form  into  true  and  degenerative  Basedow's  disease, 
according  to  whether  the  disease  develops  in  a  previously  normal  or  in  a 
neuropathic  individual.  From  the  great  group  of  formes  frustes  Stern 
separates  out  Kraus^s  goiter  heart;  the  remaining  forms  are  based  regularly 
on  an  original  degenerative  neuropathic  foundation.  Basedowoid  and 
Basedow's  according  to  this  view  are  distinguished  from  each  other  essen- 
tially by  their  beginning,  course,  and  prognosis.  According  to  Stern,  they 
never  pass  over  into  each  other.  CJivostek  agrees  with  Stern  on  the  whole, 
except  that  he  would  regard  as  formes  frustes  the  relatively  abortive  cases 
of  true  Basedow's  that  pursue  a  light  course.  Langelaan  regards  Stern's 
Basedowoid  as  Basedow's  on  an  asthenic  basis.  The  practical  significance  of 
a  clinical  differentiation  of  the  individual  formes  is  in  themselves  intelligible 
if  through  them  deductions  as  to  the  prognosis  and  therapy  can  be  given. 
On  the  other  hand.  I  would  point  out  with  emphasis  the  danger  that  exists  in 
the  fact  that  through  the  accentuation  of  the  distinguishing  features,  the 
painstakingly  wrought-out  conception  of  the  pathogenetic  unity,  the  hy- 
perthyroidal  syndrome,  is  relegated  too  much  to  the  background.  The 
same  is  true  as  to  the  statement  as  to  which  symptoms  must  be  present,  if 
we  wish  to  establish  the  diagnosis  of  hyperthyrosis,  that  is,  Basedow's  disease 
in  a  wider  sense.  It  seems  to  me  suitable  to  approach  this  question  from 
another  direction,  and  to  establish  what  symptom  or  -what  symptoms  are  con- 
stant in  artificial  thyroidism  and  the  earliest  to  appear.  According  to  our 
investigations  on  this  subject  it  appears  that  without  doubt  the  cardio- 
vascular symptoms,  especially  the  tachycardia,  here  predominate.  To  the 
tachycardia  may  be  added  sweats,  or  mononucleosis,  or  psychic  excitability, 
or  headaches,  etc.  The  symptom  that  occurs  twice  as  frequently  is  accord- 
ing to  our  observation  the  greater  moisture  of  the  skin,  which  is  absent  only 
in  rare  cases.  If  other  symptoms  are  added  to  this,  we  obtain  syndromes 
such  as  tachycardia,  sweats,  headaches,  or  tachycardia,  sweats,  tremor,  or 
tachycardia,  sweats,  mononucleosis,  etc.  Hence  by  this  route  we  come  back 
to  the  conception  of  Charcot  and  Mohius  that  just  cardiac  or  vascular  disturb- 
ances are  to  be  regarded  as  the  cardinal  symptom,  to  which  is  added  in  most 


BASEDOW  S   DISEASE  97 

cases  the  increase  in  metabolism;  with  somewhat  longer  action  of  the  hyper- 
thyroidism, tachycardia,  mononucleosis,  and  tremor  may  well  be  regarded 
as  cardinal  symptoms.  From  these  symptoms  to  pronounced  exophthalmus 
is  indeed  a  wide  stride;  probably  there  is  added  an  enormous  flooding  of 
the  blood  with  thyroid  secretion;  and  perhaps  other  constitutional  factors 
whose  nature  is  unknown  to  us.  In  the  fully  developed  cases  we  have  always 
before  us  a  marked  condition  of  excitation  of  almost  the  entire  vegetative  nervous 
system.  This  way  of  looking  at  the  subject  brings  us  back  to  Mdbius's 
view  that  all  the  syndromes  of  Basedow's  disease  have  a  common  nucleus. 
The  classic  form  of  Basedow's  is  characterized  only  by  the  more  pronounced 
accentuation  of  the  eye  symptoms,  by  a  more  considerable  increase  of  the 
metabolic  processes,  and  by  its  rapid  origin,  while  Stern's  Basedowoid  ordi- 
narily shows  from  the  beginning  an  insidious  course. 

From  both  these  forms — the  classic  form  and  the  forme  fruste — is  to  be 
delimited  sharply  only  the  Kraus-Minnich  goiter  heart.  The  newer  in- 
vestigations show  that  here  the  cardiac  disturbances  are  not  of  pure  hy- 
perthyroidal  origin,  but  that  the  goiter  noxus  is  involved  in  their  coming 
about.     I  shall  therefore  speak  of  this  form  under  cretinic  degeneration. 

Course.- — The  classic  forms  of  Basedow's  disease  as  well  as  the  formes 
f rustes  show  the  greatest  variability  in  their  course.  The  classic  form  may  de- 
velop in  the  midst  of  complete  health,  often  in  a  peracute  manner,  for  ex- 
ample, during  swimming  {Pribram)  or  a  few  hours  after  a  tonsillotomy 
(Patterson);  the  condition  may  again  return  to  normal,  with  a  disappearance 
of  the  eye  symptoms,  or  may  lead  to  death  under  stormy  manifestations  (de- 
lirium, premortal  increase  of  temperature),  or  may  go  over  into  a  chronic  form 
with  remissions  and  renewals.  It  can,  however,  after  several  years  show  a 
surprising  turn  toward  amelioration,  and  may  eventually  heal  with  the  re- 
tention of  the  exophthalmus,  which  has  now  become  definite;  relapses  of 
this  form  are  frequent;  in  other  cases  it  leads  to  severe  irreparable  cachexia. 
The  classical  form  may  also  begin  gradually  both  in  previously  normal  and 
in  neuropathically  affected  individuals,  or  may  show  quite  the  picture  of  a 
forme  fruste,  and  only  later  develop  fully  under  any  determming  factor  or 
without  ascertainable  cause. 

Among  the  formes  frustes  are  slight  abortive  cases  of  sudden  onset. 
The  cases  with  fat  stools  and  glycosuria  are  mostly  cases  of  abortive  formes 
frustes  (without  eye  symptoms).  Many  of  the  cases  that  I  observed  set  in 
after  trauma,  but  in  the  great  majority  of  formes  frustes  a  quite  gradual 
beginning  is  the  rule;  especially  in  those  forms  existing  on  a  neuropathic 
basis,  the  forms  that  Stern  designated  as  Basedowoid,  the  beginning  goes  as 
far  back  as  youth,  and  decades  may  lapse  before  the  disease  is  to  any  degree 
distinct.  In  such  characteristic  cases  the  trophic  disturbances  are  mark- 
edly prominent.  It  is  Stern's  great  service  to  have  shown  that  in  these 
cases  there  is  quoad  sanationem  a  very  favorable  prognosis.  On  the  con- 
7 


98  THE    DISEASES    OF    THE    THYROID    GLAND 

trary  I  cannot  agree  with  Stern  that  ''Basedowoid''  cases  never  go  over 
into  the  classic  form  of  Basedow's.  It  seems  to  me  that  the  t}'pical  Base- 
dow's on  a  degenerative  foundation  (Stern's  degenerative  Basedow's)  can 
hardly  be  anything  else  than  a  Basedow's  wdth  acute  exacerbations. 

The  diagnosis  of  the  classic  form  is  easy,  differential  diagnostic  diffi- 
culties presenting  only  in  the  formes  frustes.  Alcoholism  and  nicotinism 
may  produce  tachycardia  and  tremor;  the  history  or  finally  the  demonstra- 
tion of  a  central  scotoma  will  set  the  diagnosis  right  (Chvostek).  Fr.  Midler 
has  pointed  out  the  similarity  of  chronic  lead  poisoning  to  the  formes  frustes. 
Here  the  lead  line  and  the  granular  erythrocytes  will  set  matters  clear, 
although  I  have  seen  a  case  of  the  combination  of  the  two  conditions  [lead 
poisoning  and  Basedow's].  Difficulties  may  also  attend  the  decision  of  the 
question  whether  such  Basedow's  symptoms  as  tachycardia,  pigmentations, 
lability  of  the  vascular  system  which  often  accompany  such  trophoneurosis 
of  the  vegetative  nervous  system  as  scleroderma,  depend  on  a  simultaneous 
hyperthyrosis  or  the  fundamental  disease  as  such.  Cassirer  further  points 
out  that  a  slight  grade  of  exophthalmus  is  often  simulated  by  the  sclero- 
dermic mask.  The  presence  of  a  Basedow's  struma  in  four  such  cases  enables 
us  to  speak  with  probability  of  a  combination  with  Basedow's  disease. 
Most  difficult  is  the  differential  diagnosis  from  the  cardiovascidar  neurosis 
of  Chvostek  in  which  occur  tachycardia,  dermographism,  inclination  for  sweats 
and  hue-waved  tremor.  Great  lability  of  the  heart  manifestations  speak 
for  neurosis,  enlargement  of  the  thyroid  gland  and  slight  eye  symptoms, 
heightening  of  the  [metabolic]  exchange  {v.  Xoorden)  and  especially  a  mono- 
nucleosis speak  for  hyperthyroidism.  In  many  cases,  as  Chvostek  emphasizes, 
a  certain  diagnosis  can  be  first  established  from  the  course  of  the  disease. 
In  persons  that  come  to  the  physician  with  complaints  as  to  slight  emacia- 
tion, nervousness,  cardiac  palpitations,  and  psychic  excitation,  light  will 
often  be  thrown  on  the  matter  by  the  fact  that  they  have  been  using  iodine. 
For  th2  judgment  of  the  fat  stools  the  evacuation  of  unsplit  neutral  fats  and 
the  predominance  of  finely  divided  soap  balls  and  fatty  acid  needles  is  decisive. 
Evidence  for  the  diagnosis  of  a  complicating  glycosuria  is  afforded  by  the 
fact  that  the  true  thyrogenic  glycosuria  usually  is  of  slight  intensity  and 
that  with  the  improvement  or  the  retrogression  of  the  Basedow's  symp- 
toms it  not  only  disappears,  but  high  or  normal  tolerance  for  carbohydrates 
reappears  very  rapidly. 

Prognosis  and  Treatment.- — Since  the  beginning  of  the  operative  era  in 
the  treatment  of  Basedow's  disease  the  question  of  especial  interest  has  been 
whether  surgical  treatment  should  supersede  the  medical  treatment.  One 
has  but  to  consider  the  great  variabihty  in  the  course  of  Basedow's  disease 
to  understand  that  this  question  can  be  solved  only  by  great  statistical 
material.  We  must  therefore  bring  up  the  question  as  to  the  prognosis 
of  the  cases  of  Basedow's  disease  treated  purely  medically.     The  greatest 


BASEDOW  S    DISEASE  99 

difficulty  lies  in  the  fact  that  the  internist  publishes  only  the  severest,  be- 
cause interesting,  cases,  and  that  further,  this  material  comes  especially 
from  clinics  and  dispensaries,  hence  from  the  poorer  classes  of  the  popula- 
tion; and  yet  v.  Noorden  mentions  the  fact  that  the  course  of  Basedow's  disease 
is  to  a  great  extent  dependent  on  whether  the  patient  for  a  long  time  can 
be  placed  under  favorable  living  conditions  until  he  has  had  time  to  regain 
his  health.  The  material  of  the  individual  statistics  is  therefore  very 
dissimilar.  All  statements  by  the  internists  agree  on  the  one  point  that 
in  mild  forms  of  Basedow's  disease,  recovery  is  the  rule,  as  far  as  the 
patients  can  spare  time  for  a  proper  treatment  {v.  Noorden,  Oppenheim, 
Pribram,  Chvostek,  Mackenzie,  Murray,  Quine,  and  many  others).  Special 
statements  as  to  the  curability  of  severe  cases  are  not  at  hand.  The  state- 
ments as  to  curability  are  concerned  only  with  the  slight  and  severe  forms 
together.  I  mention  A.  Kocher^s  statistics  (internal  cases)  i8  per  cent., 
Syllaha's  26  per  cent..  Stern's  (of  19  cases,  9  almost  cured),  Mackenzie'' s  50 
per  cent,  (very  good  result),  Quine's  60-70  per  cent.,  Klemm''s  25  recoveries 
among  32  cases.  Just  as  difficult  is  any  idea  as  to  the  mortality  (death  from 
Basedow's  disease  itself,  not  from  intercurrent  affections).  Sattler  has  col- 
lected the  literature  that  is  not  too  one-sided,  and  arrives  at  11  per  cent., 
Kocher  states  22  per  cent.,  Leischer  and  Marburg,  12-25  per  cent.,  Mackenzie 
estimates  the  mortality  in  the  acute  cases  as  at  30  per  cent.,  in  cases  in  which 
icterus  develops,  the  prognosis  is  extremely  grave.  Between  these  two  ex- 
tremes^— recovery  and  death — lie  the  chronic  and  more  or  less  improved  cases, 
concerning  the  relationship  of  which  to  each  other  the  figures  again  vary 
widely.  Thus  Kocher  states  ^^  per  cent,  uncured,  27  per  cent,  improved; 
Syllaba  36  per  cent,  improved.  Stern,  of  19  cases  of  classic  morbus  Basedowi, 
6  with  slight  improvement,  3  uncured.  Stern  mentions  that  the  improve- 
ment may  set  in  even  after  years.  Stern'' s  work  is  of  great  practical  impor- 
tance in  so  far  as  it  shows  that  cases  on  a  degenerative-neuropathic  basis 
progress  to  full  height,  rarely  die  of  Basedow's  disease  itself,  and  on  the 
contrary,  very  rarely  recover  entirely. 

In  spite  of  the  quantity  of  the  material,  its  dissimilarity,  as  previously  men- 
tioned, gives  no  certain  result,  at  least  not  until  according  to  v.  Noorden's 
proposition  there  are  separate  statistics  as  to  the  disease  in  the  well-to-do 
and  the  poor  classes.  Before  I  go  into  the  question  of  internal  treatment  I 
would  like  to  make  a  few  remarks  as  to  the  results  of  operation.  Concern- 
ing the  method  of  operation,  it  should  be  mentioned  that  the  Hgation  of 
arteries  of  the  thyroid  gland  has  to-day  for  the  most  part  been  discarded,  be- 
cause unsafe,  and  that  enucleation  methods  are  mostly  practised,  and  some- 
times excision  and  ligation  are  combined.  The  resection  of  the  sympathetic^ 
introduced  by  Jaboulay,  practised  especially  by  Jonnescu  and  by  Abadie,  has 
found  but  little  vogue.  Lately  Berard  has  stated  that  among  40  operations, 
there  were  8  complete  cures,  5  died  at  operation,  16  retained  a  small  goiter, 


lOO  THE    DISEASES    OF    THE    THYROID    GLAND 

5  were  improved,  and  5  remained  uninfluenced.  The  latest  statistics  of 
Kocher  include  376  of  his  own  cases,  of  which  76  per  cent,  were  cured  (in  one- 
fourth  of  these  the  exophthalmus  was  retained).  The  mortality  was  3.9  per 
cent.,  the  rest  was  improved  or  not  cured;  one-third  of  these  cases  were  oper- 
ated on  more  than  once  before  the  desired  result  was  obtained.  Leischner 
and  Marburg  report  45  cases  (without  compression  symptoms)  from  v. 
Eiselherg's  cHnic,  of  which  there  were  6  cases  of  death  (3  of  the  first  4  cases 
operated  on  died),  18  cured,  8  improved.  Mayo  has  4.75  per  cent,  mortality 
in  405  cases  and  70  per  cent,  cures;  Scliultze  (Riedel)  reports  among  50  cases 
72  per  cent,  cured,  12  per  cent,  improved,  2  per  cent,  poor  results.  12  per 
cent,  deaths.  Landstrom  reports  among  38  cases  52.6  per  cent,  cured,  18.4 
per  cent,  improvement,  29  per  cent,  poor  result,  among  which  5.5  per  cent, 
death.  I  shall  not  enter  into  the  older  compilations,  they  are  less  valuable, 
as  the  methods  of  operation  have  improved  since  their  time  and  also  the 
indications  for  operation  have  changed  somewhat.  [See  the  tabulated  list  of 
operative  results  in  the  addendum  to  this  chapter.] 

If  we  consider  that  among  the  cases  operated  on  just  the  mild  cases  seem 
to  be  rare  from  the  better  situated  classes,  that  therefore  the  surgical  statistics 
contain  the  especially  severe  cases,  there  is  no  doubt  that  all  the  surgical 
treatment  in  general  surpasses  the  medical.  To  this  should  be  added  that 
after  the  operation  the  tachycardia  usually  diminishes;  in  a  relatively  short 
time,  the  body  weight  rapidly  increases,  even  without  hospital  care,  and 
working  capability  is  rapidly  attained.  The  difficult  point  of  the  question 
to-day  is  concerned  with  the  indications  for  operation.  Mild  cases  among  the 
better  situated  classes  should  indeed  not  be  recommended  operation,  nor 
should  the  chronic  formes  frustes  on  a  degenerative-neuropathic  basis  {Stern's 
Basedowoid).  Also  Kocher  points  out  that  the  results  in  these  cases  are  less 
satisfactory.  Operation  is  indicated  in  cases  with  compression  symptoms. 
In  the  cases  of  pure  Basedow's  the  social  status  should  be  decisive,  because, 
as  already  mentioned,  without  doubt,  operation  leads  more  rapidly  and 
certainly  to  working  capability.  A  certain  risk  is  always  associated  with 
operation,  especially  if  a  status  thymico-lymphaticus  is  present.  According 
to  the  statistics  of  Capelle,  already  mentioned,  nearly  100  per  cent,  of  the  cases 
of  Basedow's  disease  that  died  at  operation  had  a  hyperplastic  thymus. 
Hotz  therefore  proposed  to  avoid  operation  if  the  X-ray  transillumination 
shows  a  shadow  [indicating  an  enlarged  thymus  gland].  The  demonstra- 
tion of  an  enlarged  thymus  gland  by  means  of  the  Rontgen  procedure  is 
however  very  uncertain.  Kostlivy  believes  that  the  operation  is  especially 
dangerous  in  the  cases  without  mononucleosis.  This  does  not  however  meet 
with  my  view,  because  mononucleosis  in  the  one  and  the  same  case  may  vary 
greatly  {vide  ante).  All  these  questions  have  not  as  yet  been  worked 
out  fully. 

Another  question  is  as  to  whether  one  should  operate  early,  or  should  await 


Basedow's  disease  ioi 

the  results  of  internal  therapy.  A  long  period  of  awaiting  is  at  all  events 
unsuitable  if  the  cardiac  manifestations  are  well  pronounced,  as  operation 
represents  so  much  the  less  result  the  broader  the  cardiac  dilatation  and  the 
more  advanced  the  degenerative  alterations  of  the  cardiac  muscle  and  of  the 
other  organs.  On  the  other  hand  Kocher  recommends  a  medical  pretreat- 
ment  as  preferable,  as  far  as  no  indicatio  vitalis  does  not  make  an  immediate 
operation  necessary. 

Of  late  a  lively  discussion  has  arisen  concerning  the  reliability  or  the  value 
of  the  irradiation  of  the  thyroid  gland  with  the  X-rays.  This  was  dis- 
covered by  Beck,  first  used  in  Germany  by  Gorl,  and  is  warmly  recommended 
in  Vienna  by  Holzknecht  and  G.  Schwarz.  Schwarz  has  reported  40  cases  in 
which  after  the  irradiation  the  nervous  symptoms  always  disappeared,  and 
the  tachycardia  almost  always;  in  two-thirds  of  the  cases  there  were  gains 
in  weight,  in  about  half  the  cases  the  exophthalmus  retrogressed;  only  in  one- 
third  was  the  struma  decreased  in  size.  The  cases  that  Holzknecht  later  re- 
ported showed  a  similar  good  result,  v.  Eiselsherg  points  out,  however, 
that  in  three  of  the  cases  that  had  been  treated  with  X-rays  and  that 
he  operated  on  later,  he  found  adhesions  of  the  thyroid  gland  to  the  neigh- 
boring parts;  on  account  of  this  the  operation  was  essentially  more  difificult. 
Also  Hochenegg  reports  three  similar  cases.  It  does  not  seem  to  me  a  priori 
that  such  adhesions  are  to  be  referred  exclusively  to  the  X-ray  therapy. 
Kocher  mentions  especially  that  the  operations  of  Basedow's  strumas  are 
made  especially  difficult  through  an  especial  density  of  the  peristrumal  con- 
nective tissues,  by  adherence  of  the  external  goiter  capsule  to  the  struma, 
in  short  by  alterations  that  are  similar  to  those  of  a  chronic  inflam- 
mation and  are  often  found  in  strumas  after  a  long  treatment  with 
iodine  salve;  on  the  other  hand  it  is  to  be  expected  that  there  are  tissue 
reactions  to  X-ray  illumination  that  especially  favor  the  development  of 
such  adhesions  and  that  the  fragility  of  the  blood-vessels  constitute  a 
danger.  In  the  discussion  that  followed  Holzknechf s  presentation  in  the 
Wiener  Gesellschaft  fiir  Arzte  [Vienna  Association  of  Physicians],  v.  Noorden 
and  V.  Strumpell  assumed  an  expectant  attitude  with  regard  to  X-ray  therapy, 
while  V.  Wagner  and  Chvostek  condemned  it.  In  a  number  of  cases  that  I 
published  from  the  first  medical  clinic  since  that  time  I  have  seen  a  right  good 
result  as  the  consequence  of  X-ray  therapy. 

I  quote  the  following  example:  In  one  case  the  spontaneous  glycosuria  disappeared 
from  the  day  of  the  first  irradiation,  in  another  case  the  weight  curve,  which  in  spite  of 
week-long  hospital  treatment  had  continually  sunk,  began  to  rise  only  a  few  days  after 
the  first  irradiation,  the  diarrheas  disappeared,  and  after  a  few  weeks  the  patient  could 
again  resume  his  studies  as  technician. 

As  far  as  the  internal  treatment  of  Basedow's  disease  is  concerned,  it  must 
be  sorrowfully  said  that  all  attempts  to  find  a  specific  method  of  treatment 
have  up  to  the  present  not  led  to  certain  results.     Ballet  and  Eniquez  first 


I02  THE    DISEASES    OF    THE    THYROTD    GLAXD 

used  for  therapeutic  purposes  the  serum  of  thyroidectomized  animals, 
Biinghart  and  BlumcntJial  the  serum  of  myxedema  patients,  Sorgo  the  meat 
of  thyroidless  herbivorous  animals.  Mobius  used  the  serum  of  th^Toidless 
animals  (antithyroidin.  Merck's  preparation)  or  thyroidectin  {Parke.  Davis 
6°  Co.).  Lanz  used  the  milk  of  th}Toidless  animals  (Rodagen-milk  powder  of 
thyroidless  goats'  milk  sugar).  Lepine  obtained  an  "immune  serum"  from 
the  feeding  of  thyroidin  to  goats.  Finally  we  must  mention  the  thyro- 
toxic serum  of  Beebe.  v.  Mikulicz  recommended  the  feeding  of  thymus  sub- 
stance. All  these  therapeutic  propositions  were  for  the  most  part  greeted 
in  the  beginning  vriih  enthusiasm,  but  improvement  was  seen  only  in  the 
light  cases,  in  which  the  ameHoration  could  not  be  attended  with  certainty  by 
the  means  employed.  In  recent  years  to  have  the  statements  as  to  favor- 
able results  become  always  sparser.  The  scepsis  is  the  more  justified  for  the 
reason  that  all  authors  who  have  investigated  the  influence  of  thymus,  rodagen, 
or  antithyroidin  serum  on  the  metabolism  have  been  able  to  elicit  only  nega- 
tive results  [Magnus-Levy.  Stiive.  Salomon). — .4.  A'of//fr  recommends  neutral 
sodium  phosphate  (up  to  6  gm.  per  day),  which  should  prevent  the  dissemi- 
nation of  the  iodine-containing  substance  from  the  thyroid  gland.  Views 
do  not  agree  as  to  the  value  of  this  means  of  treatment.  Otherwise  medical 
treatment  seems  to  fail  almost  always.  All  authors  are.  for  example,  of  the 
opinion  that  digitalis  rather  aggravates  the  cardiac  conditions.  Also  the 
diarrheas  and  vomiting  are  but  little  influenced  by  drugs. 

V.  Midler  and  Saxl  proceeding  from  the  experimental  elicitation  of  Loeb, 
and  of  FrdJilich  and  Chiari  that  calcium  exercises  a  dampening  influence  on 
certain  conditions  of  irritation  of  the  nervous  system,  have  used  in  Basedow's 
disease  intramuscular  injections  of  calcium  chloride  gelatine  (5-7  cc.  of 
Merck's  preparation  '"Kalzine").  They  found  in  the  t\pical  cases  mostly 
an  essential  improvement,  while  the  treatment  usually  seems  to  fail  in  the 
case  of  an  heredito-neuropathic  basis. 

The  dietetic  and  physical  treatment  of  Basedow's  disease  still  occupies  the 
central  place  of  internal  therapy.  Most  important  is  rest,  in  the  severest 
cases  rest  in  bed  and  the  avoidance  of  every  excitement,  combined  with  the 
dietetic  treatment;  beneficial  is  the  action  of  slight  hydrotherapeutic  pro- 
cedures, such  as  were  first  recommended  by  Winternitz.  eventually  slight  gal- 
vanization and  faradization  of  the  sympathetic,  especially  in  strumas  rich  in 
blood-vessels,  and  the  air  of  heights  (6co-iooo  m.).  Xow  a  few  words  as  to 
dietetic  treatment.  In  the  first  place  this  must  tend  to  prevent  loss  of 
weight  and  to  enable  gain  in  weight.  As  in  Basedow's  disease  there  exists  an 
increased  exchange,  it  was  beheved  that  this  could  be  made  up  by  an  abun- 
dance of  protein  food.  On  the  basis  of  our  own  investigations  we  were  how- 
ever compelled  to  accept  the  idea  that  administration  of  protein  increases  the 
secretion  of  the  thyroid  gland.  With  this  stands  in  harmony  the  fact  that 
on  administration  of  meat  in  experiments,  we  can  make  the  thyroid  gland 


ATHYROSIS  OR  HYPOTHYROSIS  IO3 

extremely  poor  in  iodine,  thus  bringing  the  stored  secretion  into  the  cir- 
culation on  account  of  the  greater  need.  I  refer  once  more  to  the  experi- 
ments of  Rudinger  carried  out  on  the  basis  of  these  convictions,  which 
showed  that  on  almost  protein-free  diet,  very  rich,  however,  in  carbohy- 
drates, we  can  depress  the  increased  exchange  to  the  normal.  When  there- 
fore we  administer  abundant  nitrogen-free  energy  carriers,  we  do  not  have 
to  fear  a  loss  of  protein.  From  such  a  diet  should  be  expected  not  only 
a  favorable  influencing  of  the  body  weight,  but  also  a  certain  mitigating  in- 
fluence on  the  h}'persecretion  of  the  thyroid  gland;  to  which  must  be  added 
that  such  a  diet  oppresses  the  least  the  gastrointestinal  tract.  As  important 
as  must  be  our  endeavors  to  increase  the  body  weight  in  Basedow's,  not  the 
less  importantis  the  avoidance  of  overfeeding  {v.  Noorden),  as  the  improvement 
of  the  cardiac  activity  does  not  keep  pace  with  the  increase  of  weight,  and 
cases  are  known  in  which  the  increased  demands  on  the  heart,  in  consequence 
of  the  increase  of  weight,  led  to  a  sudden  collapse. 

b.  Athyrosis  or  Hypothyrosis 

Historical. — The  first  experiments  as  to  the  influence  of  extirpation 
of  the  thyroid  gland  on  the  animal  organism  originated  with  Schiff.  To 
about  the  same  time  belong  also  the  first  clinical  descriptions  of  myxedema 
on  the  part  of  Gull.  Ord.  and  CJiarcot.  Gull,  in  1873,  described  five  cases  of 
''A  Cretinoid  State  supervening  in  Adult  Life  in  Women.''  Ord,  in  1878, 
was  the  first  to  designate  such  cases  as  '"myxedema."  Charcot,  in  1879, 
called  the  attention  of  the  French  to  this  clinical  picture,  terming  it  "cachexia 
pachydermique.""  The  demonstration  of  the  connection  of  this  disease  with 
the  absence  of  thyroid  function  was  furnished  in  1882  and  1883,  by  Th. 
Kocher  and  Reverdin.  In  the  period  that  followed  this,  thought  was  rendered 
confused  by  the  fact  that  the  symptoms  following  upon  the  removal  of  the 
parathyroids  together  with  the  thyroid  were  attributed  to  the  absence  of  the 
thyroid.  Investigation  distinguished  between  acute  and  chronic  cachexia 
thyreopriva.  Only  at  the  end  of  the  nineteenth  century  did  the  clinical 
pictures  of  athyrosis  assume  stabile  forms,  through  the  detachment  of  the 
symptoms  due  to  the  absence  of  the  parathyroids  (Gley,  Vassale  a^ndGenerali, 
Erdheim.  Pineles.  Biedl).  About  this  time,  too,  Hertoghe  called  attention 
to  the  mitigated  forms  of  athyrosis.  To-day  one  of  the  hardest  problems 
is  the  relation  of  mjo^edema  to  cretinic  degeneration.  Although  the  fact  that 
congenital  absence  of  the  thyroid  as  well  as  a  severe  disease  of  this  organ 
in  early  life  (infantile  myxedema)  had  been  established  by  animal  experi- 
mentation and  the  recognition  of  the  significance  of  thyroaplasia  by  Pineles 
in  1902,  the  careful  analysis  of  the  clinical  manifestations  between  sporadic 
and  endemic  cretinism  permit  a  recognition  of  far-reaching  dift'erences. 
Among  these  is  the  fact  that  in  the  first  condition  thyroid  therapy  is  always 


I04  THE    DISEASES    OP    THE    THYROID    GLAXD 

successful  in  the  latter  it  sometimes  fails.  While  we  must  ascribe  certain 
of  the  important  symptoms  of  endemic  cretinism  to  thyroid  insufficiency, 
many  facts  speak  for  the  separate  position  of  this  illness. 

I  shall  first  describe  those  clinical  pictures  that  develop  through  the  failure 
of  the  thyroid-gland  function  in  the  fully  developed  organism  because  here 
the  relations  may  be  supervised  more  readily. 

I.  Myxoedema  Adultorum  or  Cachexia  Thyreopriva  Adultonim 

Definition. — This  condition,  resulting  from  the  absence  or  insufficiency  of 
the  function  of  the  thyroid  gland  in  the  adult  organism,  is  characterized  by 
tJie  diminution  of  all  vital  processes  and  by  certain  trophic  manifestations.  The 
diminution  affects  the  vegetative  functions  as  well  as  the  psychic  life.  There 
is  found  sloiving  of  the  entire  metabolism  and  diminution  of  the  excitability  of 
the  whole  vegetative  nervous  system.  The  trophic  disturbances  affect  especially 
the  ectodermal  tissues,  skin,  hair,  nails,  and  teeth,  although  almost  all  organs  may 
show  regressive  metamorphoses,  especially  the  vascular  system,  which  tends  to 
be  the  seat  of  a  premature  arteriosclerosis. 

Occurrence. — Spontaneous  myxedema  of  adults  is  a  rare  disease  that  is 
found  somewhat  more  commonly  in  England  and  Holland  [than  on  the  conti- 
nent]. In  goiter  districts  typical  myxedema  seems  to  be  relatively  rare. 
Hereditary  and  familial  occurrence  is  described  by  some  authors  {Maclll- 
waine.  Ewald.  et  al.). 

Symptomatology. — I  begin  with  the  description  of  the  alterations  in  the 
skin,  the  most  important  of  which  has  furnished  for  the  disease  its  name 
myxedema.  The  myxedematous  swelling  may  affect  the  skin  of  the  entire 
body;  it  shows,  however,  a  predilection  for  certain  sites,  the  cheeks,  lids, 
nose,  supraclavicular  fossae,  neck,  backs  of  the  hands  and  feet.  The  cheeks 
become  yellowish  in  color,  but  on  account  of  small  venectases  are  colored 
bluish-red  in  the  middle.  The  nose  and  lips  are  also  of  this  bluish-red 
color.  On  account  of  the  swelling  of  the  eyelids  the  palpebral  fissures  are 
much  narrowed,  and  the  deficient  play  of  the  features  makes  the  expression 
of  the  face  rigid  and  sleepy.  In  the  supraclavicular  fossae  develop  thick 
cushions  or  pads  that  feel  granular  to  palpation.  The  cushion-like  swelling 
of  the  backs  of  the  hands  and  feet  make  the  extremities  appear  claw-like. 

For  the  most  part  the  swelling  invades  also  the  mucous  membranes,  the 
mucous  membrane  of  the  mouth  assuming  a  whitish  color,  while  the  par- 
ticipation of  the  mucosa  of  the  larynx  leads  to  alterations  of  the  voice;  this 
becomes  harsh  and,  according  to  Magnus-Levy,  singing  becomes  impossible. 
The  swelling  of  the  uvula  and  the  tonsils  makes  nasal  breathing  impossible; 
the  patients  breathe  with  open  mouth  and  snore  at  night.  The  Eustachian 
tube  and  the  t}Tnpanic  cavity  may  also  become  involved  by  the  swelling, 
causing  a  diminution  in  hearing-ability;  and  finally  the  female  genitalia 
and  the  anus  may  become  swollen.     The  tongue  increases  greatly  in  volume, 


MYXEDEMA  IO5 

SO  that  it  becomes  visible  between  the  rows  of  teeth,  and  shows  impressions 
of  the  teeth.  The  increase  in  volume  depends  not  only  on  the  swelling  of 
the  lingual  mucosa  but  also  on  alterations  in  the  more  deeply  lying  parts. 
Histological  examination  shows  alterations  of  the  muscle  fibers  and  increase 
in  connective  tissue;  the  latter  contains  numerous  nuclei  and  numerous  new 
formed  capillary  vessels.  The  tongue  papillee,  too,  become  hypertrophic 
(Maccone) . 

The  myxedematous  skin  looks  like  alabaster.  It  feels  elastic,  pressure 
with  the  finger  evinces  no  pitting.  It  is  dry  and  scales  very  much;  the  scales 
are  mostly  clayey.  Stevenson  and  Halliburton  ascribe  the  clay-like  texture 
of  the  skin  to  the  increased  contents  in  mucin.  They  found  the  mucin- 
contents  also  increased  in  the  salivary  glands  and  tendons.  Halliburton 
found  in  the  blood  and  in  the  parotid  of  thyroprivic  monkeys  that  the  albu- 
minous bodies  precipitating  to  acetic  acid  amount  to  3  per  cent.,  while  they 
were  not  demonstrable  in  the  blood  of  normal  monkeys.  Munk  also 
found  mucin  in  the  parotid  secretion  of  a  case  of  myxedema  described  by 
Mendel.  But  other  authors  found  that  the  mucin-contents  of  the  myxede- 
matous skin  was  not  increased,  while  Bourneville  maintains  that  in  the 
investigations  just  mentioned  it  is  not  certain  that  the  substance  dealt 
with  was  mucin,  as  in  his  investigations  no  reducing  substance  was  yielded 
by  decomposition  by  means  of  acid.  The  microscopical  investigation  of  the 
myxedematous  skin  shows  nuclear  proliferation  and  new  formation  of 'con- 
nective-tissue fibrils,  especially  around  the  sweat-glands  and  sebaceous  glands 
and  around  the  hair  follicles  (English  Myxedema  Commission,  Virchow). 
Unna  found  in  skin  of  myxedemics  substances  that  stained  similarly  to 
mucin,  while  v.  Wagner  and  Schlagenhaufer  found  them  in  the  skins  of 
endemically  cretinoid  dogs  and  thyroprivic  goats.  A  substance  similar  to 
mucin  could  also  be  observed  {Halliburton  and  Scholz)  in  other  organs,  such 
as  the  kidney,  the  muscles,  and  the  brain.  That  presence  of  this  substance 
similar  to  mucin  was  missed  by  certain  authors  has  perhaps  its  explanation 
in  the  fact  that  the  accumulations  of  this  substance  are  subject  to  much 
variation,  and  in  cases  of  long  standing  they  sometimes  disappear.  The 
skin  then  regains  a  flaccid  lax  texture  and,  in  contradistinction  to  typical 
myxedematous  skin,  can  be  moved  about  on  the  underlying  tissue. 

Pigmentations  of  the  skin  occur  relatively  rarely. 

The  hair  of  the  head  and  beard,  the  eyebrows,  the  axillary  and  pubic 
hairs  become  dry  and  brittle,  and  often,  in  part,  fall  out.  On  the  skull 
then  develop  large  bald  spots,  that  may  lead  to  complete  baldness.  The 
nails  become  dry  and  cracked,  the  teeth  become  carious  and  fall  out,  and 
in  the  case  to  be  described  (Observation  XII)  the  crowns  of  the  teeth,  in  the 
course  of  the  year  that  the  myxedema  had  existed,  had  ground  off  entirely. 
The  incisor  teeth  consisted  of  only  short  stumps  provided  with  broad  grind- 
ing surfaces. 


io6 


THE    DISEASES    OF    THE    THYROID    GLAND 


The  circulation  is  sluggish,  the  body  temperature  reduces,  the  patients 
are  chilly,  and  can  warm  themselves  with  difficulty.  The  pulse  is  small 
and  weak  and  slow — often  only  50  to  60  beats  a  minute  are  observed. 
On  body  movements,  dyspnea  readily  occurs. 


Fig.  10. — Postoperative  myxedema. 

The  excitability  of  the  entire  vegetative  nervous  system  and  especially  that  of 
the  nerves  regulating  the  heart  is  diminished. 

I  here  quote  the  clinical  history  of  two  myxedema  patients  in  whom 
experiments  were  made  as  to  the  excitability  of  the  vegetative  nerves. 

Observation  XI. — Karoline  K.,  sixty-four  years,  single.     Entered  clinic  Nov.,  1913. 
One  uncle  and  one  aunt  on  the  mother's  side  suffered  with  struma.     Asa  young  girl  the 


MYXEDEMA  107 

patient  had  a  large  neck,  and  of  late  years  this  has  increased,  producing  difficulty  in  swal- 
lowing, difficulty  in  breathing,  and  indeed  attacks  of  suffocation,  on  which  account  the 
patient  was  operated  on  in  June,  1909.  Xine  days  after  the  operation  the  patient  was 
entirely  well.  In  IMarch,  19 10,  the  hands  and  feet  began  to  swell,  the  condition  being 
taken  for  rheumatism.  In  the  summer  of  1910,  myxedema  was  diagnosed,  and  an  order 
given  for  thyroid  tablets.  Under  this  treatment  the  swellings  retrogressed,  but  the 
patient  became  thin  (loss  of  weight  of  9  kg.  in  five  weeks)  and  developed  a  marked  tremor. 

At  present  are  seen  sweUings  of  the  backs  of  the  hands  and  feet,  of  the  supraclavicular 
fossae,  and  also  of  the  face,  especially  in  the  vicinity  of  the  eyes.  The  pulse  is  about  70. 
The  skin  is  drj-  to  the  touch. 

o.oi  gm.  pilocarpine  subcutaneously;  after  one-half  hour  slight  flow  of  saliva,  no 
sweat. 

100  gm.  grape-sugar,  no  dextrose  in  the  urine. 

150  gm.  grape-sugar,  no  dextrose  in  the  urine. 

Leucocytes,  6200,  of  which: 

Polymorphonuclear  neutrophiles,  62.6  per  cent. 

Eosinophiles,  5  per  cent. 

Lymphocytes  and  large  mononuclears,  32.4  per  cent. 

After  the  instillation  of  homatropine  into  the  eye.  mydriasis  occurs  after  about  forty- 
eight  hours. 

A  fully  normal  sella  turcica  to  Rontgen  examination. 

In  addition  to  the  myxedematous  manifestations  are  present  slight  signs  of  a  primary 
chronic  articular  rheumatism  (dry  form). 

Moderate  constipation. 

Observation  XII. — Schw.  F.,  thirty-eight  years,  entered  September,  1910.  First  men- 
struated at  twelve  years  of  age.  The  flow  was  always  regular  and  abundant.  Two 
labors;  since  the  last  (eight  years  ago),  which  was  followed  by  a  hemorrhage,  the  menses 
have  ceased.  Since  this  time  very  poor  appetite,  patient  always  constipated.  For  one 
year  the  hands  and  feet  often  seem  as  if  asleep,  sensation  of  cold,  formication  in  hands 
and  feet.  Speech  has  become  slower.  Often  vertigo.  Status:  Skin  pale,  thickened  and 
dry  to  the  touch,  hands  cool,  hairs  thinned  out  and  dry.  Teeth  small  and  loose,  the 
chewing  surfaces  much  worn  down,  so  that  the  teeth  are  reduced  to  about  one-half 
their  length.  In  the  axiUse  and  on  the  pubis  the  hairs  are  entirely  absent.  The  facial 
expression  is  slightly  catatonic,  both  lobes  of  the  thyroid  are  palpable,  internal  genitalia 
atrophic,  blood-pressure  very  low  (between  60  and  70,  Gartner),  o.ooi  gm.^  adrenalin 
subcutaneously;  no  glycosuria,  no  increase  in  blood-pressure. 

100  gm.  dextrose  by  mouth  and  at  the  same  time  0.002  gm.^  adrenalin  subcutaneousty; 
no  glycosuria. 

0.01  gm.  pilocarpine;  no  salivation,  sweating  very  slight.  Slight  increase  in  blood- 
pressure. 

Erythrocj-tes,  3,500.000. 

Hemoglobin,  70  per  cent. 

Leucocytes  7000,  of  which: 

Polymorphonuclear  neutrophile,  52  per  cent. 

Lymphocytes  and  large  mononuclears,  42  per  cent. 

Eosinophiles,  6  per  cent. 

After  the  instillation  of  homatropine,  mydriasis  occurs  after  about  thirty-six  hours. 

From  the  middle  of  October,  thyroid  tablets.  At  the  beginning  of  November  swelling 
of  the  face  has  disappeared,  the  skin  about  the  eyes  and  on  the  clavicles  ver}-  loose, 
facial  expression  very  much  livelier,  hands  now  warm  and  less  cyanotic. 

^  German  edition  states  mg.  [  =  milligram];  evident!}'  gm.  is  intended. — Editor. 


Io8  THE    DISEASES    OF    THE    THYROID    GLAND 

A  diminution  in  the  excitability  of  the  vegetative  nervous  system  is 
demonstrated  also  by  the  experimental  investigations  in  thyroidless  animals. 
V.  Cyon  found  a  diminution  of  the  excitability  to  electrical  stimulation  of 
the  vagi  nerves  in  such  animals.  The  hyperexcitability  of  the  accelerator 
nerves  that  he  asserted  to  be  present  could  not  be  confirmed.  It  is  far  more 
likely  that  the  excitability  of  the  sympathetic  nerves  is  diminished.  For 
this  view  speaks  the  failure  of  the  glycosuric  action  of  adrenalin  in  thyroid- 
ectomized  animals  and  in  myxedema  patients.  As  regards  the  diminution 
of  the  pressor  action  of  adrenalin  we  {Eppinger,  Falta,  and  Rudinger)  did  not 
arrive  at  a  certain  result;  while  on  the  contrary,  later  investigations  of 
Bertelli  and  myself  show  definite  alterations  in  the  reaction  of  the  vascular 
system  of  thyroidless  dogs  against  adrenalin. 

As  I  regard  the  experiments  important,  I  shall  quote  them  in  extenso. 

15  kg.  dog,  ten  days  ago  total  extirpation  of  the  thyroid  gland  with 
avoidance  of  the  parathyroids.     Electrical  excitability  remains  unaltered. 

Erythrocytes       ,        Hemoglobin        j    Specific  gravity 


60  per  cent. 

1050 

65  per  cent. 

1055 

63  per  cent. 

IOS5 

55  per  cent. 

1052 

Before  the  injection 4,900,000  45  per  cent,      j  1054 

5  hours  after  the  infusion  of  3.69  mg.  adrenalin         4,100,000       ;     45  per  cent.      '  1050 

24  hours  after  this 3,936,000       |     45  per  cent.      |  1051 

Dog,  16  kg.,  total  extirpation  of  the  thyroid  six  weeks  ago.  Electrical 
excitability  remains  unaltered. 

Erythrocytes       ,        Hemoglobin        ,     Specific  gravity 

_  __  ^  ^  ^ 

Before  the  injection 5,056,000 

i}'^  hours  after  infusion  of  3.69  mg 5,932,000 

5  hours  after 5,680,000 

72  hours  after 5,016,000 

According  to  investigations  of  Bertelli,  Schweiger,  and  myself,  the  erythro- 
cyte count  in  normal  dogs  after  the  injection  of  adrenalin  increases  extra- 
ordinarily rapidly;  after  ten  minutes  it  may  reach  40  per  cent.,  after  five 
hours  70  per  cent.  In  an  experiment  in  which  4.36  mg.  adrenalin  was 
injected,  it  reached  100  per  cent,  after  twenty-four  hours;  in  another 
experiment  after  3.69  mg.  the  hyperglobulia  was  indeed  distinct,  but  had 
already  begun  markedly  to  decline.  Although  of  course  there  occurred  indi- 
vidual differences  in  the  intensity  and  duration  of  the  reaction,  there  was  to 
be  observed  in  all  normal  dogs  a  distinct  rise.  The  hemoglobin  contents 
showed  a  very  much  less  increase.  The  specific  gravity  regularly  showed  a 
slight  increase. 

While,  then,  normal  animals  show  after  injection  of  adrenalin  a  high- 
grade  hyperglobulia,  in  the  production  of  which  there  is  surely  concerned, 


MYXEDEMA  IO9 

in  addition  to  alterations  in  the  permeability  of  the  endothelium  of  the  blood- 
vessels, also  the  pressing  out  of  plasma  on  account  of  the  long-continued 
contracted  condition  of  the  vessels,  this  manifestation  was  absolutely  lacking 
or  was  essentially  weaker  in  the  thyroidless  dogs.  In  this  respect,  individuals 
without  thyroids  show  similarity  to  individuals  with  cachexia,  who,  as  is 
known,  do  not  react  with  hyperglobulia  to  the  use  of  the  lung  suction-mask, 
or  to  sudden  transference  to  great  heights. 

The  autonomous  nerves  too  show  a  diminution  of  their  tonus  and  their 
excitability,  v.  Cyon  observed,  as  already  mentioned,  a  diminution  of  the 
electrical  excitability  of  the  vagi.  The  miotic  action  of  pilocarpine  in  thy- 
roidless dogs  lasts  for  a  shorter  tim'e  [Eppinger,  Falta,  and  Riidinger).  The 
observations  of  A  slier  have  already  shown  that  in  dogs  with  thyroid  insuffi- 
ciency the  mydriatic  action  of  atropine  lasts  for  an  abnormally  long  time. 
Hence  the  autonomous  nerves  are  more  readily  paralyzed  than  under  nor- 
mal relations.  Also  in  blood-pressure  investigations  on  thyroidless  dogs 
Rudinger  and  /  observed  that  ruling  out  of  the  vagi  through  atropine  lasts 
extraordinarily  long.  Finally,  in  some  cases  of  myxedema  I  could  estab- 
lish an  abnormally  long  mydriatic  action  on  the  instillation  of  homatropine 
into  the  eye  (confer  the  analogous  experiments  in  sporadic  cretinism). 
Fleischmann  observed  that  the  blood  of  normal  animals  destroys  the  activ- 
ity of  added  atropine  more  rapidly  than  the  blood  of  strumous  animals. 

The  previously  mentioned  alteration  in  the  reaction  of  the  vascular  endo- 
thelium to  adrenalin  depends  perhaps  on  the  disturbances  in  nutrition,  and 
these  could  be  the  cause  of  the  premature  arteriosclerosis  of  thyroidless 
animals,  such  as  Eiselsberg,  Pick,  Pineles,  and  others  have  described.  Also  in 
myxedema  patients  we  frequently  find  striking  grades  of  arteriosclerosis 
and  depositions  of  lime  salts,  the  latter  even  in  other  organs,  such  as  the 
kidney,  liver,  etc.  {Ahrikosof).  Finally  also  in  thyroaplasia  has  high- 
grade  atheroma  been  found  in  the  aorta  and  other  vascular  territories 
(Bourneville,  Maresch,  Machand,  Heyn,  and  others) .  The  occurrence  of  arterio- 
sclerotic alterations  in  thyroid-gland  insufficiency  has  been  brought  forward 
as  the  explanation  of  the  senile  degeneration.  Horsley  first  pointed  out  that 
the  thyroid  gland  in  old  age  becomes  atrophic,  Vermehren  compares  old  age 
with  a  chronic  myxedema,  while  in  more  recent  times  Lorand  has  elaborated 
on  this  view.  In  opposition  to  this,  Ewald  has  already  shown  that  in  maras- 
mus senilis  there  is  initiated  not  only  an  atrophy  of  the  thyroid  (and  the 
other  ductless  glands)  but  also  a  degenerative  atrophy  of  the  other  organs, 
especially  the  gastrointestinal  tract.  At  all  events,  we  should  not  use  thy- 
roid medication  in  old  age  uncritically  (v.  Noorden). 

The  diminution  of  the  tonus  or  the  excitabihty  of  the  vegetative  nerves 
is  spoken  for  also  by  the  failure  of  the  sweat  secretion  in  myxedema  patients. 
The  secretion  of  sweat  may  fail  entirely  on  bodily  movements,  or  even  when 
there   exists   high   external   temperature.     Mann    observed    that   in   myx- 


no  THE    DISEASES    OF    THE    THYROID    GLAND 

edemics  infusion  of  jaborandi  did  not  bring  about  secretion  of  sweat.  I, 
too,  observed,  in  the  above-mentioned  cases,  after  pilocarpine  injection 
only  slight  salivation  and  no  or  only  minimal  sweating.  In  myxedema  there 
is  also  a  diminution  of  the  function  of  the  sebaceous  glands  (deficient  oiling 
of  the  skin  and  hair) .  I  have  not  been  able  to  find  in  the  literature  statements 
as  to  the  secretion  of  gastric  juice  or  pancreatic  juice. 

To  a  slight  tonus  of  the  autonomous  nerves  points  the  high-grade  atony 
of  the  intestines  that  is  the  cause  of  the  well-known  obstipation  of  myxedema 
patients.  Defecation  in  well-developed  cases,  if  purgatives  be  not  employed, 
may  not  occur  for  two  or  three  weeks. 

Almost  constantly  do  alterations  of  the  psychic  functions  accompany 
myxedema.  The  English  IVlyxedema  Commission  found  the  apathy  char- 
acteristic of  myxedema  absent  in  only  three  of  one  hundred  and  nine  cases. 
This  may  develop  relatively  early,  and  in  the  light  cases  may  consist  only 
in  a  sluggishness  of  the  previously  mentally  and  bodily  active  patients, 
in  a  retardation  of  the  psychic  functions,  in  an  inability  to  form  rapid  conclu- 
sions and  in  a  slowing  and  monotony  of  the  speech.  According  to  Magnus- 
Levy,  in  light  cases  the  "capability  of  reacting  to  strong  stimuli"  is  for  the 
most  part  not  lost.  In  more  well-developed  cases  there  is  a  complete  dullness, 
the  patients  brood,  and  there  exists  marked  desire  for  sleep.  The  speech 
may  be  markedly  slowed  "als  ob  die  Sprachwerkzeuge  eingefroren  waren" 
[as  if  the  speech-mechanism  were  frozen  in]  (Meltzer).  C/iarcot  compares 
such  patients  to  hibernating  animals.  In  such  individuals,  too,  the  intellect 
tends  to  deteriorate  and  the  memory,  especially  that  for  recent  occurrences, 
is  lost. 

In  such  high-grade  cases  there  are  rarely  lacking,  in  addition  to  this 
decided  apathy,  signs  of  a  more  deeply  seated  mental  disturbance.  Already 
at  the  beginning  of  the  myxedematous  disease  or  in  the  formes  frustes  are 
hallucinations  commonly  present,  concerning  which,  as  Murray  says,  the 
patient  does  not  willingly  speak. 

The  English  IMyxedema  Commission  found  among  the  myxedema  patients 
investigated  by  them  illusions  i8  times,  hallucinations  i6  times,  and  a 
frank  psychosis  i6  times.  The  psychoses  belong  to  various  types,  although 
the  melancholoid  conditions  predominate;  and  may  of  course  consist  only  of 
a  combination  with  myxedema.  Very  commonly,  however,  they  stand  in  an 
intimate  relation  with  myxedema  in  this  respect — that  through  the  myxedema 
a  previously  existing  predisposition  becomes  manifest.  In  these  cases  the 
symptoms  of  the  psychosis  develop  simultaneously  with  those  of  the  myxe- 
dema and  vanish  after  thyroid  therapy  has  been  instituted,  to  reappear 
again  when  the  therapy  is  discontinued.  Such  a  case  has  been  described  by 
Pilcz.  In  many  cases,  especially  at  the  beginning,  the  inhibition  is  suddenly 
interrupted,  and  the  condition  may  transitorily  go  as  far  as  excitation. 
Horsley  distinguished  between  a  neurotic  stage  that  occurs  at  first,  and  a 


MYXEDEMA  III 

myxedematous  or  cretinoid  stage,  although  this  distinction  may  have 
been  influenced  by  the  tetanoid  manifestations  after  thyroid-gland  extirpa- 
tion which  at  that  time  were  ascribed  to  the  absence  of  the  thyroid. 

Other  coarse  disturbances  that  are  routinely  looked  for  on  the  investiga- 
tion of  the  nervous  status  are  not  as  a  rule  found.  The  reflexes  are  for  the 
most  part  normal,  only  rarely  are  they  increased  or  diminished.  Not 
rarely  the  patients  complain  of  paresthesias  and  of  rheumatic  pains.  The 
test  for  sensibility  for  the  most  part  normal,  at  the  most  it  has  been 
stated  that  slowing  of  conduction  is  present,  although  this  finding  is  by  no 
means  constant.  It  has  been  recognized  that  testing  of  sensation  is  hard  to 
carry  out  in  heavily  apathetic  patients.  The  same  holds  good  for  tests  of 
the  smell,  taste,  and  hearing.  Most  common  of  these  disturbances  are  those 
of  hearing.  These  were  found  by  the  English  Commission  in  almost  half  of 
the  cases  it  investigated.  The  cause  for  them  has  not  as  yet  been  certainly 
ascertained.  Wagner  v.  Jauregg  assumes  that  they  are  produced  by  myxe- 
dematous swelling  of  the  mucous  membrane  of  the  tympanic  cavity  and  the 
tube.  It  is,  however,  often  very  hard  to  determine  what  part  the  lessened 
power  of  apprehension  of  the  central  apparatus  and  the  lacking  appercep- 
tion plays  in  this;  in  any  case  it  is  significant  that  the  disturbances  of  hearing 
react  promptly  to  thyroid  medication. 

The  conductivity  of  the  skin  for  the  electric  current  is  diminished  on 
account  of  the  high  degree  of  dryness.  Authorities  also  state  that  in  many 
cases  there  is  diminution  of  the  electrical  excitability  of  the  nerves  and 
muscles.  In  one  case  Erb  found  it  normal.  Rudinger  and  myself  found 
an  appreciable  diminution  of  the  galvanic  excitability  of  the  nerves  in 
thyroidless  dogs.  The  investigation  was  conducted  three  months  to  one  and 
one-half  years  after  extirpation  of  the  thyroid.  Instead  of  the  normal  value 
of  1. 2-1. 5  milliamperes  we  needed  2-3  milliamperes  in  order  to  produce  (test 
of  the  sciatic  nerve)  a  cathodal  closing  contraction.  In  one  case  of  myxedema 
Erh  found  a  slow  twitching  of  the  muscle  to  mechanical  irritation.  The 
motor  processes,  too,  are  conducted  slowly.  The  movements  are  extremely 
slowed,  the  gait  heavy,  slow,  and  slightly  staggering.  One  of  the  early 
symptoms  is  a  rapid  tiring,  only  on  the  longer  duration  of  the  disease  is  the 
motor  power  diminished.  The  cause  of  all  alterations  in  function  of  the 
central  and  vegetative  nervous  system  lies  in  nutritive  disturbances.  W alter , 
and  Marinesco  and  Minea  found  in  thyroidless  dogs  a  slowing  of  degeneration 
and  regeneration  of  the  nerves. 

There  is  not  much  known  concerning  alterations  in  the  osseous  system 
in  myxedema.  Stuhenrauch  describes  in  a  case  symmetrical  changes  of 
the  bones  and  joints  of  the  feet.  Both  first  interphalangeal  joints  were 
destroyed,  the  middle  and  end  phalanges  showed  in  part  abnormal  transpar- 
ence and  in  certain  places  direct  loss  of  substance.     In  the  absence  of  further 


112  THE    DISEASES    OF    THE    THYROID    GL.A^yTD 

observations,  we  should  be  cautious  about  bringing  such  alterations  into 
relationship  with  myxedema. 

The  examination  of  the  blood  shows  decrease  of  the  red  cells,  and  es- 
pecially of  the  hemoglobin,  the  latter  to  60  per  cent,  or  even  40  per  cent.; 
also  decrease  in  the  dry  residue  and  increased  coagulability  {BuUschenko  and 
Drinkmann,  Kottman).  The  leucocytic  formula  is  altered,  consisting  in 
mononucleosis  and  mostly  hypereosinophilia  (Bence  and  Engel,  and  the 
author) . 

In  many  cases  are  observed  erythroblasts  and  slight  poikilocytosis, 
in  others  also  Turk's  irritation  forms  and  myeloblasts.  In  one  of  the  cases 
herein  quoted  were  found  indeed  isolated  myeloblasts.  Similar  blood  changes 
are  also  found  in  thyroprivic  animals  (z^.  Eiselsberg,  Zitschnann,  Kishi, 
Esser,  BertillVs  investigations  on  our  own  dogs).  The  anemia  quickly 
ameliorates  on  the  administration  of  thyroid-gland  substance,  and  there 
occurs  a  "paradoxical"  reaction  of  the  leucocytes,  i.e.,  the  leucocytic  formula 
approaches  the  normal,  while  in  healthy  individuals  it  is  known  that  thy- 
roidin  produces  mononucleosis  (Falta,  Xewhurgh,  and  Xohel).  More  recent 
investigations  of  Fonio  agree  with  these;  interruption  of  the  thyroid-gland 
therapy  for  the  most  part  brings  about  a  recurrence  of  the  mononucleosis 
{von  Korczynski) ,  while  the  poverty  in  hemoglobin  also  is  essentially  amelio- 
rated by  the  thyroid-gland  therapy. 

Tne  metabolism  of  myxedemics  is  reduced  to  a  marked  degree.  We  are 
indebted  to  Magnus-Levy  for  the  discovery  of  this.  He  found  a  reduction 
of  the  fundamental  exchange  to  58  per  cent.  Treatment  with  thyroidin 
brings  the  fundamental  exchange  to  normal  or  supernormal  figures. 

If  the  thyroid-gland  therapy  be  interrupted,  the  amount  of  oxygen  con- 
sumed gradually  sinks  as  the  clinical  symptoms  recur.  Also  the  twenty- 
four-hour  exchange  is  reduced,  that  is,  myxedemics  maintain  an  equilibrium 
with  a  much  less  amount  of  calories  and  take  on  fat  more  readily  than 
does  the  normal  individual. 

Sometimes  accumulations  of  fat  are  found  at  entirely  abnormal  sites. 
Thus  Ahrikosof  found  in  a  fifty- two-year  myxedematous  woman  accumula- 
tions of  fat  in  the  lingual  mucous  membrane  and  in  the  submucosa  of  the 
intestine.  If  myxedemics  are  nourished  abundantly,  the  twenty-four-hour 
exchange  does  not  necessarily  have  to  be  below  normal,  and  thyroidin 
administration  will  then  produce  an  enormous  increase  in  the  caloric  pro- 
duction. Steyrer  found  in  his  case  an  increase  of  83  per  cent,  (investiga- 
tion in  Voit-Peltenkofer's  apparatus).  Especially  fat  is  concerned,  while  the 
number  of  calories  from  protein  is  rather  less  than  normal.  Again,  the  pro- 
tein exchange  lies  low,  the  protein  requirements  are  light,  and  there  may 
be  an  addition  of  protein  to  the  body.  The  relations  in  investigations  as 
to  the  hunger  protein  exchange  are  very  clear.  In  thyroidless  dogs  we 
found  this  distinctlv  reduced. 


MYXEDEMA  II3 

The  time  consumed  in  the  protein  destruction  in  thyroidless  dogs  is, 
according  to  the  investigations  of  Pari,  not  altered.  Administration  of 
thyroidin  leads,  in  the  wake  of  the  consumption  of  myxedematous  tissue,  at 
first  to  a  significant  increase  of  the  nitrogen  excretion,  this  giving  place  to 
normal  relations.  The  relations  of  the  salt  metabolism  in  myxedemics  is 
not  as  yet  fully  explained;  it  is  to  be  expected  that  the  need  for  salt  is  slighter 
and  that  less  calcium  is  cast  off  in  the  feces,  as  the  administration  of  thy- 
roidin allows  more  calcium  to  pass  out  through  the  intestine.  The  amounts 
of  urine  in  myxedemics  as  a  rule  are  very  small.  Often  slight  albuminuria 
is  found,  that  may  probably  be  attributed  to  nutritive  disturbances  in  the 
kidneys. 

The  assimilation  limits  for  grape-sugar,  in  myxedemics,  is  raised  {Hirschl, 
Knopf elmacher) .  Hirschl  found  no  glycosuria  even  after  the  administration 
of  500  gm.  of  dextrose.  Also  in  thyroprivic  dogs  the  administration  of  sugar 
(up  to  200  gm.)  does  not  lead  to  glycosuria,  although  in  dogs  the  assimilation 
limits  lie  relatively  low.  In  thyroprivic  dogs  the  glycosuric  action  of 
adrenalin  is  reduced  {Eppinger,  Falta,  and  Rudinger,  Pick  and  Pineles)} 
Myxedemics  show  the  same  relation. 

In  a  case  of  Herz's  the  administration  of  dextrose  with  the  simultaneous 
injection  of  adrenalin  did  not  lead  to  glycosuria.  I  found  the  same  thing  in 
the  case  described  above  (Observation  XII)  (loo  gm.  dextrose  together 
with  the  simultaneous  administration  of  2  mg.  adrenalin  subcutaneously) . 
After  a  long-continued  thyroidin  medication  the  relations  become  normal 
again.  In  the  case  of  Herz,  after  successful  thyroidin  treatment,  traces  of 
sugar  appeared  in  the  urine  after  only  100  gm.  of  dextrose.  Adrenalin  now 
again  produced  glycosuria. 

The  inclination  to  glycosuria  can  also  remain  after  the  withdrawal  of 
thyroidin  treatment.     As  example  I  quote  the  following  case: 

Observation  XIII. — Rosa  L.  Entered  the  clinic  June,  1895,  then  fifty-two  years  old. 
From  the  history  taken  at  the  time,  three  confinements,  first  menstruation  at  the  age  of 
fifteen  years.  After  the  confinement  the  menses  were  irregular  and  sparse,  and  ceased 
three  years  ago.  Then  abdominal  pains,  jaundice,  followed  by  a  marked  swelling  of  the 
neck  that  gradually  retrogressed  again.  Since  that  time  there  has  gradually  developed, 
especially  since  the  winter  of  this  year,  the  following  disease-condition;  great  languor, 
rapid  fatigability,  rheumatoid  pain,  swelling  of  the  upper  and  lower  extremities,  the 
face,  the  eyelids,  hoarseness  of  the  voice,  constipation  and  distention  of  the  abdomen, 
bloated  condition  of  the  face,  swelling  of  the  lips,  tongue,  and  eyelids.  The  swelling  of 
the  tongue  and  lips  is  so  intense  that  it  hinders  eating.  There  are  subjective  sensations 
of  cold,  especially  on  the  back.  Often  severe  headaches,  sensation  of  vacancy  in  the  head, 
and  feeling  of  anxiety. 

From  the  status:  Skin  of  the  extremities  and  on  the  abdomen  thick,  cool,  and  cyanotic. 

^  The  alimentary  glycosuria  that  is  observed  in  thyroparathyroprivic  dogs  (Falckenherg, 
R.  Hirsch)  is  to  be  ascribed  to  the  absence  of  the  function  of  the  parathyroids.  (Confer  also 
Falta  and  Rudinger.) 


114  THE    DISEASES    OF    THE    THYROID    GLAND 

There  are  present  on  the  upper  and  lower  extremities,  and  in  part  on  the  trunk,  signs 
of  ichthyosis.  The  face,  and  especially  the  eyelids,  are  swollen  out,  so  that  the  skin  in  the 
vicinity  of  the  ej'es  is  markedly  wrinkled.  The  facial  expression  is  exquisitely  sleepy, 
the  forehead  transversely  wrinkled  so  that  an  astonished  expression  is  produced;  the  hairs 
are  dry  and  very  much  thinned  out  (of  late  years  especially  have  fallen  out).  Face 
somewhat  markedly  pigmented,  lips  protruded  in  a  somewhat  snout-like  manner,  the 
teeth  for  the  most  part  are  missing  or  are  loose.  In  both  supraclavicular  fossae  slight 
cushion  formation.  On  the  left  the  lateral  lobe  of  the  thyroid  somewhat  palpable. 
Great  drowsiness,  and  slowness  of  all  movements.  Speech  very  slow.  Weakness  of 
memory.  Gait  awkward,  dragging.  Great  fatigability.  The  patient  was  given  at  times 
thyroidin  tablets,  which  however  produced  cardiac  palpitations  and  turned  the  constipa- 
tion into  diarrhea.  However,  under  this  treatment  the  swellings  disappeared  very  rapidly. 
In  1897  she  tried  thyroidin  tablets,  without  deleterious  effects.     She  took  them  ordinarily 


Fig.   II. — Case  of  myxedema  with  tendency  to  gl^xosuria. 

for  about  fourteen  days,  during  which  time  she  lost  weight  rapidly,  then  she  would  dis- 
continue them  for  about  four  weeks,  until  the  pockets  on  the  eyelids  and  the  thickenings 
on  the  abdomen  appeared  again.  In  1895  the  patient  was  almost  bald;  later  the  hair 
grew  again  and  at  present  she  has  a  growth  of  hair  about  usual  for  a  woman  of  her  age. 
She  perspires  hardly  at  all.  For  two  months  she  has  again  discontinued  the  thyroidin 
medication,  and  all  the  above-mentioned  manifestations  have  recurred  to  an  exaggerated 
degree.  After  100  gm.  of  grape-sugar  the  patient  shows  a  distinct  although  not  very 
strong  glycosuria;  sharply  delimited  cyanosis  of  the  cheeks. 

There  is  indeed  no  doubt  that  since  the  year  1895  the  patient  has  suflfered  from  a 
typical  myxedema.  Perhaps  at  that  time  a  thyroiditis  appeared  together  with  the 
jaundice,  which  gradually  led  to  insufficiency  of  the  thyroid  gland.  The  combination  with 
ichthyosis  had  been  often  described  by  French  authors.  From  the  beginning,  the  case 
showed  no  high  tolerance  for  thyroidin.  although  there  was  already  present  a  myodegen- 
eratio  cordis.  I  can  readily  appreciate  that  in  such  cases  palpitations  can  occur  even 
when  the  doses  are  not  too  high. 

The  observation  that  the  alimentarj^  glycosuria  resulted  positive,  in  spite  of  the  two 
months'  cessation  of  thyroidin  medication,  points  to  the  fact  that  here,  in  addition  to  the 
thyroid  gland,  the  pancreatic  insular  apparatus  is  also  degenerated. 


MYXEDEMA  115 

In  this  case  I  prescribed  small  doses  of  thj^roidin,  and  at  the  same  time  hypophysis 
tablets,  as  I  suspected  a  degeneration  of  the  glandular  portion  of  the  hj^pophysis  also. 
I  need  only  mention  the  fact  that  this  medication  was  borne  for  several  months  without 
calling  forth  the  previous  cardiac  distresses,  and  that  thereby  the  recurrence  of  the  myxe- 
dema symptoms  was  prevented.  The  puffiness  on  the  neck  and  face  had  disappeared, 
the  scaHng  of  the  skin  which  has  existed  for  eighteen  years  has  disappeared,  the  skin  has 
become  smooth  and  elastic,  the  itching  has  ameHorated;  only  the  brittleness  of  the  nails 
has  remained  unaltered  (communication  by  letter). 

The  explanation  for  the  simultaneous  existence  of  myxedema  and  an 
inclination  to  glycosuria  that  I  sought  in  this  case  would  serve  also  for  any 
case  that  under  thyroid  therapy  proceeded  to  spontaneous  glycosuria 
{Macfie  Camphell,  Bramu'ell.  Ewald,  Osier,  et  al.),  or  that  without  thyroid 
therapy  showed  a  tendency  to  glycosuria  (Gamier  and  Lehret).  Also  com- 
binations of  myxedema  and  diabetes  are  observed,  but  indeed  appear  to  be 
very  rare.  The  case  of  A  pert  was  that  of  sporadic  cretinism  with  distinct 
myxedematous  manifestations.  In  this  case  growth  ceased  only  at  the  age 
of  thirty-six  years.  Later,  diabetes  appeared.  I  beheve  that  it  is  intelligible 
that  absence  or  insufficiency  of  the  function  of  the  thyroid  leads  toh}'perfunc- 
tion  of  the  pancreatic  insular  apparatus  only  when  this  is  capable  of  function- 
ating. If  the  pancreas  itself  is  diseased,  diabetes  may  occur,  even  when  the 
thyroid  fails.  This  is  shown  by  the  experiments  of  Eppinger,  Rudinger.  and 
myself  on  the  pancreatic  diabetes  of  thyroidless  dogs.  If,  however,  m^-xe- 
dema  is  superadded  to  an  already  present  glycosuria,  the  glycosuria  tends 
to  disappear.  Thus  v.  Xoorden  reports  fourteen  cases  of  endogenous  obe- 
sity, of  whom  seven  formerly  excreted  shght  quantities  of  sugar.  With 
the  development  of  the  forme  fruste  of  myxedema  the  sugar  disappeared, 
and  even  a  high  tolerance  for  carbohydrates  commenced.  Only  in  one  case 
did  the  glycosuria  persist,  in  mild  form,  during  the  myxedema. 

The  diminution  in  the  general  metabolicprocesses  in m}'xedema  expresses 
itself  also  in  liypothermia;  this  belongs  to  the  commonest  symptoms  of  the 
fully  developed  forms.  The  rectal  temperature  varies  between  36°  and  37° 
Celsius,  and  may  even  be  below  36''.  It  stands  in  relationship  with  the 
sensations  of  cold  complained  of  by  the  patients.  IM}-xedemics  feel  com- 
fortable only  when  the  external  temperature  is  high;  their  condition  aggra- 
vates in  the  cold  season  of  the  year;  it  has  even  been  stated  that  in  summer 
time  we  ma}'  need  to  administer  smaller  doses  of  thyroid-gland  substance 
in  order  to  compensate  for  the  deficiency,  and  must  increase  the  dose  in 
winter.  Strong  stimuli,  as  for  example,  infectious  diseases,  may,  however, 
also  bring  about  h}-perthermia,  as  numerous  examples  in  the  literature  bear 
witness. 

In  severe  cases  of  myxedema  there  regularly  develop  disturbances  in 
the  sphere  of  the  genitalia.  Women  develop  irregularities  of  menstruation; 
either  the  menses  cease  or  there  occur  profuse  floodings.  In  the  long-stand- 
ing cases  premature  climacteric  occurs,  and  often  a  high  degree  of  atrophy 


Il6  THE    DISEASES    OF    THE    THYROID    GLAND 

of  the  genital  apparatus  {Landau,  Szanto).  In  two  women  with  distinct 
cachexia  strumipriva,  Langhans  found  pronounced  small-cystic  degenera- 
tion of  the  ovaries.  Allen  Starr,  Kirk,  Schotten  and  after  them  many  others 
have  testified  to  the  occurrence  of  menorrhagia.  In  men,  libido  is  lost. 
Very  instructive  in  this  connection  is  a  case  of  Magnus-Levy,  in  which  a  fifty- 
four-year-old  man  lost  libido  completely,  and  regained  it  after  cure  of  his  ill- 
ness. Herz  observed  a  similar  case  in  which  a  forty-five-year-old  man  re- 
gained erections  and  ejaculations  two  weeks  after  the  beginning  of  treatment. 
Treatment  by  thyroid  gland  also  affects  favorably  the  menstrual  disturbances 
in  women.  These  do  not  signify  sterility,  as  there  are  cases  of  myxedema 
that  become  normally  pregnant.  It  is  shown  also  by  animal  experimenta- 
tion [Halsted)  that  partial  extirpation  of  the  thyroid  does  not  prevent  normal 
carrying  of  young.  In  such  cases  the  thyroids  of  the  fetuses  seemed  to  act 
compensatorily.  In  other  words,  Halsted  observed  in  the  new-born  pups 
an  enormous  hypertrophy  of  this  organ.  The  thyroids  were  about  twenty 
times  as  large  as  in  a  normal  new-born  pup.  In  cases  with  a  long-standing 
high-grade  deficiency  of  thyroid  function,  there  occurs  atrophy  of  the  ovaries. 
In  this  case  the  disturbance  seems  to  be  irreparable. 

In  cases  of  myxedema  the  hypophysis  is  commonly  described  as  altered. 
Boyce  and  Beadles  found  enlargement  of  this  organ,  as  did  also  Ponfick  in  a 
case.  In  a  case  of  Ahrikosoff s  the  glandular  portion  of  the  hypophysis  was 
enlarged,  and  indeed  the  chromophilic  cell-columns  were  increased,  the  cells 
enlarged,  their  protoplasm  showing  colloid  degeneration.  Comte  earlier  ob- 
served a  similar  condition  and  considered  the  enlargement  of  the  hypophysis 
as  a  compensatory  hypertrophy.  In  other  cases  there  has  occurred  a 
pronounced  sclerotic  degeneration  of  the  glandular  hypophysis  (2nd  case  of 
Ponfick)  or  cystic  degeneration  {Sainton  and  Rathery,  and  others).  In  both 
the  cases  of  myxedema  above  reported  sella  turcica  as  shown  by  X-ray 
was  normal. 

An  enlargement  of  the  hypophysis  after  extirpation  of  the  thyroid  has 
been  observed  in  animal  experimentation.  In  growm  animals,  Bertelli  and 
myself  (reports  not  published  in  detail)  could  not  find  anything  similar  after 
a  one  and  one-half  years'  duration  of  the  thyroprivic  condition.  I  think 
that  the  findings  described  are  overestimated  as  to  their  significance  for  the 
reciprocal  action  between  thyroid  gland  and  the  glandular  hypophysis.  The 
vicarious  action  of  the  hypophysis  for  the  thyroid  gland,  as  Comte  assumed, 
need  not  be  considered  in  this  connection.  It  is  just  as  if  in  contracted 
kidney  the  liver  acts  vicariously  for  the  kidney.  In  myxedema  adultorum 
the  hypophysis  sustains  mostly  changes  of  a  strumous  character,  or  simultane- 
ously with  these,  changes  of  a  chronic  inflammatory  nature  (as  for  example 
in  the  cases  of  Ponfick,  Sainton  and  Rathery,  et  al.),  such  as  we  shall  meet 
with  again  in  the  consideration  of  multiple  ductless  glandular  sclerosis. 
Simultaneous  disease  of  the  thyroid  gland  and  the  glandular  hypophysis 


MYXEDEMA  II7 

(pathological  correlation)  is  very  rare.  I  shall  deal  with  it  in  detail  in  the 
chapter  on  the  hypophysis.  Often  in  such  cases  thyroid-gland  medication 
causes  a  disappearance  of  only  a  portion  of  the  cachectic  symptoms.  We 
shall  deal  later  with  the  alterations  in  the  hypophysis  in  infantile  myxe- 
dema. The  combination  of  myxedema  with  tetany  is  considered  in  the 
fourth  chapter. 

Etiology  and  Course. — We  to-day  possess  a  complete  explanation  of  the 
etiology  of  myxedema  operations.  Total  extirpation  of  the  thyroid  gland 
always  leads  to  myxedema,  which  in  very  rare  cases  may  be  only  slight 
and  may  heal  spontaneously,  this  manifestation  being  due  to  the  compen- 
satory hj^pertrophy  of  accessory  thyroids  (cases  of  Vollmann  and  Reverdin). 
It  is  very  noteworthy  that  in  cases  of  accessory  struma  of  the  base  of  the 
tongue,  extirpation  of  the  tongue  struma  led  to  myxedema.  Seldowitsch 
and  Chamisso  have  each  reported  such  a  case.  After  operations  for  struma, 
mitigated  forms  of  myxedema  operations  often  appear,  forms  that  show;,  for 
example,  only  disturbances  of  growth,  or  only  fat  deposits,  or  only  apathy. 
Among  thirty-eight  cases  of  cachexia  strumipriva,  Kocher  saw  the  miti- 
gated form  only  nine  times;  here  recurrences  of  the  goiters  developed. 
If  a  thorough  continual  treatment  with  thyroidin  be  not  instituted  there  is 
shortening  of  the  thyroidectomized  individual's  life.  Total  thyroidectomies 
are  to-day  still  performed  only  on  malignant  degenerations  of  the  thyroid 
gland.  ^Mitigated  operative  myxedema  may  also  occur  to-day  w^here  there 
is  intense  degeneration  of  the  part  left  behind. 

The  pathologico-anatomical  finding  in  the  thyroid  in  so-called  spontaneous 
myxedema  is  ordinarily  sclerosis  with  destruction,  or  a  high-grade  goitrous 
degeneration.  In  many  cases  of  spontaneous  myxedema  only  fat  and  con- 
nective tissue  [Ahrikosof)  is  found  on  the  site  of  the  thyroid.  Only  in  rare 
cases  is  the  etiology  of  the  inflammatory  cirrhosis  clear,  as  for  example  in 
Kohler's  cases  of  syphilis  and  actinomycosis  respectively  of  the  thyroid,  the 
first  yielding  to  the  effects  of  potassium  iodide,  the  latter  to  operation,  v. 
Wagner  observed  two  cases  of  formes  frustes  in  the  eruptive  stage  of  syphilis; 
in  the  later  stages  of  sj^ohilis  infiltrates  and  gummata  are  present.  Tuber- 
culosis of  the  thyroid  gland  is  relatively  not  very  common.  Also  miliary 
tuberculosis  has  been  observed.  Primary  tuberous  tuberculosis  seems  to  be 
very  rare.  In  certain  cases  of  multiple  sclerosis  of  the  ductless  glands  there  is 
found  in  the  thyroid,  in  addition  to  difl'use  chronic  processes,  also,  in  some 
places,  tuberculous  foci.  In  most  of  the  cases  of  spontaneous  myxedema 
there  were  perhaps  other  infections  than  those  stated.  The  territory  has 
not  as  yet  been  explored  bacteriologically.  An  index  is  furnished  by  those 
cases  of  myxedema  that  appear  after  cases  of  infectious  diseases.  Thus 
Reinlinger  reports  a  case  of  an  individual,  twenty-two  years  old,  who  after 
a  gastric  fever  (t}^hoid?)  developed  cachexia,  myxedema  of  the  skin,  apathy, 
dementia,  and  falling  out  of  the  axillary  and  pubic  hair.     Thyroid  therapy 


Il8  THE    DISEASES    OF    THE    THYROID    GLAND 

produced  good  results.  Marfan  saw  myxedema  develop  after  an  acute  artic- 
ular rheumatism  with  angina.  Sometimes,  as  previously  mentioned,  the  hy- 
perplasia of  Basedow's  disease  goes  over  into  atrophy.  The  investigations 
of  Roger  and  Gamier,  de  Quervain,  Sarbach,  Bayon,  and  others  have  shown, 
however,  that  in  severe  infections  diseases  there  regularly  develop  in  the 
thyroid  inflammatory  processes,  and  in  chronic  intoxications  cirrhotic 
processes. 

The  reason  that  myxedema  is  commoner  in  women  than  in  men  should 
be  sought  in  the  fact  that  the  normal  sexual  processes  in  women  determine 
an  important  affection  of  the  function  of  the  thyroid,  and  that  an  exhaustion 
of  this  is  produced  the  more  easily  by  damages  to  the  parenchyma  due  to 
common  infections  or  intoxications.  For  this  assumption  speaks  the  fact 
that  mitigated  forms  of  hypothyrosis  tend  to  become  worse  during  pregnancy 
and  that  not  rarely  the  myxedematous  symptoms  disappear  at  the  sexual 
involution. 

Finally,  it  should  here  be  mentioned  that  sclerotic  processes  are  found 
in  the  thyroid  in  numerous  cases  of  scleroderma  {Singer,  Hektoen,  Roux, 
Leredde  and  Thomas,  and  others).  Eventually,  in  many  cases  of  sclero- 
derma are  found  also  symptoms  that  remind  one  of  myxedema  (Cresset, 
Osier,  and  others).  As  scleroderma  involves  in  sympathy  the  most  diverse 
organs,  we  readily  see  that  we  should  best  regard  the  alterations  in 
the  thyroid  as  a  partial  phenomenon  of  the  fundamental  processes  (see 
Chapter  I). 

Differential  diagnosis  is  concerned  first  of  all  with  nephritic  edema. 
Slight  presence  of  albumin  [in  the  urine]  may  also  occur  in  myxedema.  We 
should  especially  consider  the  density  of  the  swellings,  the  failure  of  hyper- 
tonia, and  the  presence  of  psychic  alterations.  Also,  in  myxedema,  the 
swellings  are  often  more  distinct  in  the  morning  than  in  the  evenings. 

Stabile  erysipeloid  edema,  indurative  syphilitic  edema,  and  pachyderma 
are  distinguished  from  myxedema  by  normal  psychic  relations ;  nor  do  they 
react  to  administration  of  thyroidin.  Thyroid  medication  may  affect 
favorably  scleroderma  (stimulation  of  metabolism,  Ewald) ;  the  same  holds 
good  of  certain  cases  of  lipomatosis  dolorosa  {Dercum) .  In  many  such  cases 
alterations  are  found  in  the  thyroid,  in  others  in  the  hypophysis  (see 
Chapter  XIV). 

The  incomplete  forms  of  myxedema  are  of  difficult  diagnosis.  Hertoghe 
first  drew  attention  to  these,  designating  them  chronic  benign  hypothyroid- 
ism. They  are  much  commoner  and  more  multiform  in  women.  They  often 
begin  with  chronic  muscular  pain,  which  may  disturb  sleep.  Rachialgias 
are  especially  frequent,  to  which  may  be  added  great  lassitude,  especially 
in  the  morning  hours,  menstrual  disturbances,  menorrhagias  or  amenorrhea, 
sensation  of  cold,  even  shiverings,  hoarseness  of  the  voice,  and,  especially 
often,  rather  obstinate  constipation.     The  picture  becomes    clearer   when 


MYXEDEMA  II9 

the  hair  begins  to  fall  out,  especially  the  hairs  over  the  occiput,  and  when 
apathy  and  depression  are  added.  Sometimes  many  persons  in  the  same 
family  are  found  with  the  signs  of  chronic  mitigated  thyroid  insufficiency. 
Hertoghe  mentions  that  pronounced  signs  of  myxedema  in  children  first 
drew  his  attention  to  the  signs  mentioned  in  the  mother,  and  that  thyroid 
treatment  of  the  mother  brought  about  good  results.  Gluzinski  remarks 
that  such  abortive  forms  of  myxedema  in  women  occur  not  rarely  in  the 
years  just  before  the  climacteric  and  retrogress  when  the  climacteric  has 
been  completed.  The  last  statement  has  also  been  mentioned  by  Hertoghe. 
Kocher  and  Fr.  Kraus  agree  with  Hertoghe  concerning  the  frequency  of  such 
forms.  Kocher  mentions  that  manifestations  of  chronic  rheumatism  that 
are  associated  with  pains,  stiffness,  and  heaviness  of  the  extremities  not 
infrequently  depend  upon  a  larval  hypothyrosis.  The  diagnosis  may  also  be 
made  more  difficult  by  the  fact  that  distentions  of  the  joints  develop.  Parhan 
and  Papiniam  have  described  a  case  of  chronic  rheumatism  which  they  re- 
garded as  dysthyrogenic.  Rothschild  and  Levi  have  tried  thyroid  therapy 
on  a  large  group  of  cases  of  chronic  articular  rheumatism.  There  were 
twenty  moderately  severe  and  light  cases  among  thirty-nine  cases  varying 
from  twelve  to  fifteen  years  of  age.  Of  these,  eighteen  were  cured  or  es- 
sentially improved,  while  of  the  severe  cases,  two  were  cured  and  thirteen 
improved.  One  should  be  very  careful  about  regarding  these  forms  of  articu- 
lar rheumatism  as  thyrogenic,  as  it  is  not  unlikely  that  good  results  may  be 
brought  about  solely  by  the  stimulation  of  the  metabolism  through  the 
thyroid  medication. 

Hertoghe  certainly  goes  too  far  when  he  brings  myomata,  retroflexion 
of  the  uterus,  emphysema,  congestion  of  the  liver,  and  gall-stone  formation 
directly  into  relation  with  the  thyroid  gland  insufficiency  {Kocher,  Fr. 
Kraus).  That  on  the  other  hand  we  were  justified  in  ascribing,  in  many 
cases,  the  above-cited  manifold  disturbances  to  a  chronic  light  thyroid 
insufficiency  speaks  the  fact,  quite  apart  from  therapeutic  results,  that  Kocher 
not  rarely  saw  such  "thyroprivic  equivalents"  occur  after  strumectomy. 

The  diagnosis  of  such  benign  forms  of  thyroid-gland  insufficiency  can, 
as  can  readily  be  understood,  present  great  difficulties,  especially  when  only 
a  few  of  the  manifold  symptoms  are  present,  for  instance,  increased 
heaviness  of  the  nasal  breathing,  hoarseness  of  the  voice,  or  a  slight  degree 
of  deafness.  Especial  attention  is  to  be  directed  in  these  cases  to  the 
presence  of  pseudolipomata  in  the  supraclavicular  fossce  or  to  transverse 
folds  in  the  forehead  {y.  Wagner).  Often  the  diagnosis  can  onl}^  be  made 
tentatively  ex  juvantibus. 

An  especial  form  of  mitigated  thyroid  insufi&ciency  is  thyrogenic  obesity. 
In  contradistinction  to  so-called  dietary  obesity  there  are  cases  in  which 
obesity  develops  in  spite  of  slight  supply  of  calories,  and  remains  present 
when  the  supply  of  calories  is  so  restricted  that  normal  individuals  of  the 


I20  THE    DISEASES    OF    THE    THYROID    GLAND 

same  size,  of  the  same  weight,  and  under  the  same  living  conditions  would 
rapidly  lose  in  bodily  weight  under  such  conditions.  The  cause  of  endoge- 
nous obesity  is  of  yery  diverse  nature  (see  also  Chapter  VI,  on  the  hypophysis, 
and  the  various  forms  of  obesity,  Chapter  XIV).  But  it  can  hardly  be 
doubted  that  one  of  these  causes  is  a  slight  grade  of  thyroid  insufhciency. 
The  thyrogenous  obesity  may  depend  on  inherited  predisposition  or  may 
follow  infectious  diseases  (v.  Noorden).  Also  it  may  be  preceded  by  a  Base- 
dow's disease.  I  refer  to  the  cases  of  Basedow's  disease  in  which  the  initial 
emaciation  is  followed  by  a  progressive  increase  in  weight.  For  the  diagnosis 
of  thyrogenous  obesity,  important  also  are  other  symptoms  such  as  phlegma 
and  constipation,  especially  if  they  have  existed  before  the  development  of 
obesity.  Such  cases  belong  in  the  domain  of  thyroid  treatment;  restriction 
of  calories  in  such  cases  can,  especially  in  older  persons,  lead  to  a  marked 
exhaustion  and  cardiac  collapse,  without  lessening  the  amount  of  fat,  while 
administration  of  thyroid  gland  reduces  the  body  weight  with  amelioration 
of  the  general  condition  {v.  Noorden). 

The  cause  of  the  manifoldness  of  the  hypothyroidal  syndrome  may  be  re- 
garded, as  in  the  hyperthyroidal  syndrome,  as  differences  in  the  constitutions 
of  the  individuals  aft'ected. 

The  course  of  myxedema  in  untreated  cases  may  be  progressive  and  give 
rise  to  a  cachexia;  then  intercurrent  affections  often  occur,  and  lead  to 
death.  Spontaneous  improvement  may  also  occur,  not  rarely  with  the 
development  of  a  goiter,  in  rare  cases  with  hypertrophy  of  the  accessory 
thyroid  glands. 

The  treatment  of  myxedema  will  be  considered  after  the  description  of 
sporadic  cretinism. 

2.  Sporadic  Cretinism 

Definition.— In  the  preceding  section  we  drew  disease  pictures  that 
originate  in  an  organism  already  fully  developed,  when  the  thyroid  becomes 
insufficient  or  loses  its  function  entirely.  When  the  disturbance  in  thyroid 
function  develops  in  an  organism  as  yet  unfinished,  there  occur  in  addition 
profound  developmental  disturbances  that  are  the  more  intense  the  earlier 
the  disturbance  begins.  The  conception  of  sporadic  cretinism  as  hypo- 
thyrosis  or  athyrosis  of  the  youthful  organism  is  decisively  proved  in  the  first 
place  by  the  sad  experiences  that  were  sometimes  met  with  at  a  time  when  the 
functions  of  the  thyroid  were  not  known,  in  strumectomies  on  children,  and  in 
the  second  place  by  the  fundamental  researches  on  total  extirpation  of  the 
thyroid  in  animals  (of  Hojmeister  and  of  v.  Eiselsherg).  The  thyroprivic 
animals  oiv.  Eiselsherg  that  were  kept  under  the  same  conditions  as  the  control 
animals  showed  after  a  few  weeks,  as  against  the  control  animals  of  the  same 
brood,  a  considerable  remaining  behind  in  size  and  in  body  weight.  The  dis- 
turbance in  growth  affected  more  the  long  bones  than  the  trunk.     The  bones 


SPORADIC    CRETINISM  121 

became  coarse  and  showed  decrease  in  solidity.  After  a  longer  time  the 
bodily  weight  of  the  control  animal  often  attained  to  three  times  that  of  the 
thyroprivic  animal.  In  addition  were  found  distention  of  the  abdomen, 
anemia,  atheromatous  degenerations  of  the  great  vessels,  atrophy  of  the  geni- 
talia, reduction  in  temperature,  curving  of  the  bones,  trophic  alterations  of 
the  hair,  dryness  of  the  skin,  senile  marasmus,  and  pronounced  idiocy,  in 
short  the  picture  of  idiotic  dwarfism.  The  changes  in  human  beings  when  the 
function  of  the  thyroid  becomes  deficient  in  early  life  are  entirely  analogous. 
The  lack  of  thyroid  may  be  either  congenital  {thyroaplasia  or  thyrohypoplasia) 
or  the  same  changes  that  cause  myxedema  of  adults  may  affect  the  thyroid  in 
early  life  [spontaneous  infantile  myxedema),  or,  as  already  mentioned,  a 
surgical  procedure  may  lead  to  thyroid  insufficiency  {postoperative  infantile 
myxedema) . 

Pineles,  who  was  the  first  to  separate  thyroaplasia  from  the  entire  group 
as  an  etiologically  unitary  form,  wished  to  avoid  the  expression  sporadic 
cretinism  and  to  distinguish  only  between  thyroaplasia  and  infantile 
myxedema.  It  seems  to  me,  however,  that  this  sharp  distinction  is  not 
practicable.  It  is  true  that  infantile  myxedema  makes  its  first  appearance 
in  the  fifth  or  sixth  year  of  life,  while  in  thyroaplasia  the  exhibition  of  develop- 
ment begins  gradually  to  manifest  itself  already  in  the  first  year  of  life. 
Infantile  myxedema  may,  however,  also  develop  at  the  earliest  age.  If 
the  damage  to  the  thyroid  in  these  cases  is  a  material  damage,  the  intensity 
of  the  inhibition  of  development  is  the  same  as  in  thyroaplasia,  and  as  the 
finding  on  palpation  when  negative  is  not  decisive,  so  a  certain  differentiation 
between  these  two  conditions  is  hardly  attainable  in  vivo,  especially  if  the 
individuals  first  undergo  an  exact  physical  examination  at  a  later  stage  of  Hfe. 
I  therefore  wish  to  retain  the  name  sporadic  cretinism  for  the  entire  group. 
Siegert  erhbraces  all  the  cases  of  lack  or  deficiency  of  the  thyroid  gland  in 
children,  together  with  endemic  cretinism,  under  the  name  myxidiotie 
[myxidiocy].  As  I  do  not  regard  endemic  and  sporadic  cretinism  as  entirely 
of  similar  nature,  I  cannot  subscribe  to  this  designation. 

In  his  excellent  work  on  thyroaplasia,  Pineles  collects  from  the  older  litera- 
ture twelve  cases  in  which  the  thyroid  was  absent  microscopically  at  autopsy. 
Almost  all  the  individuals  affected  died  at  an  early  age;  in  the  fewer  older 
individuals  who  had  attained  the  age  of  puberty  it  seems  that  the  demonstra- 
tion of  a  complete  aplasia  of  the  thyroid  was  not  certain,  or  the  cases  had  been 
treated  with  thyroid  tablets  [MacCallum  and  Fabyan).  Also  Thomas  Erwin 
remarks  this.  In  the  case  oi  Fletcher-Beach,  that  concerned  a  fifteen-year-old 
girl,  a  certain  intelligence  had  developed.  She  had  learned  to  write  and  use 
figures,  and  had  menstruated  two  or  three  times.  The  autopsy  indeed 
showed  absence  of  the  thyroid  gland,  but  as  such  a  development  is  hardly 
possible  with  a  complete  thyroaplasia — the  publication  of  this  case  occurs 
before  the  era  of  thyroid-gland  therapy — it  is  possible  that  here  accessory 


122  THE    DISEASES    OF    THE    THYROID    GLAND 

thyroids  were  present,  which  could  not,  however,  fully  compensate  the 
deficiency.  Pineles  then  cites  seven  works  of  a  more  recent  date  in  which  an 
exact  microscopical  examination  failed  to  find  any  remnants  of  thyroid  gland 
(Kocher-Langhans,  Muratov,  Maresch,  Peucker,  AscJwJf,  Erdheim,  Knopjel- 
macher).  The  case  of  Maresch  was  that  of  an  eleven-year-old  girl  whose 
brothers  and  sisters  were  perfectly  well;  according  to  the  statements  of  the 
parents,  growth  ceased  almost  entirely  at  one  and  a  half  years  of  age.  At 
eleven  years  of  age,  the  girl  was  77  cm.  tall,  the  skull  had  a  circumference  of 
49  cm.,  the  abdomen  53  cm.,  the  great  fontanelle  measured  4)^  cm.  by 
i3^  cm.  The  girl  could  not  walk,  could  only  sit,  and  could  speak  only  a  few 
syllables.  The  skin  was  myxedematous  (also  on  microscopical  examination), 
the  hypophysis  was  of  normal  size,  the  thymus  gland  corresponded  with  the 
age.     Pancreas  and  suprarenals  were  of  normal  size. 

The  contribution  of  Maresch  was  of  fundamental  importance,  because 
Maresch  established  for  the  first  time  in  his  case  the  presence  of  the  parathy- 
roid glands.  Also  later  investigators  found  the  parathyroid  glands  intact. 
Only  in  a  few  cases  was  the  simultaneous  absence  of  parathyroid  glands  re- 
ported {Quincke,  Case  I,  Rocazet  Cruchet,  two  cases  of  Siegert).  Here,  how- 
ever, no  serial  sections  were  made. 

Very  exactly  studied  are  the  cases  of  Aschoff,  of  Erdheim,  and  of  Dieterle. 

The  case  of  Aschoff  was  that  of  a  half-year-old  child  of  53  cm.  length. 
The  hypophysis  was  very  much  enlarged  (0.5  gm. ) .  Aschoff  found  at  the  root 
of  the  tongue  a  cystic  tumor  that  he  regarded  as  the  remnant  of  the  lingual 
duct.  In  addition,  there  was  found  at  the  site  of  the  lateral  thyroid  lobe  a 
half-pea-sized  vesicle  that  he  regarded  as  the  remnant  of  the  branchial  pouch. 
The  case  of  Erdheim  was  a  thirteen-month-old  child,  the  thirteenth  child  of 
healthy  parents.  High-grade  constipation  had  been  present  (palpable  fecal 
tumor).  Here  also  was  found  the  vesicle  as  in  the  case  of  Aschoff;  micro- 
scopical examination  showed  that  it  consisted  of  an  ectodermal  formation, 
as  to  the  origin  of  which  from  the  fourth  branchial  pouch  there  could  be  no 
question,  as  Erdheim  found  the  same  cysts  on  this  side  in  two  cases  of 
unilateral  thyroaplasia,  in  which  cysts  on  the  normal  side  were  absent. 

Very  recently  have  been  added  the  cases  of  Ungermann  (vicarious  tongue- 
struma),  MacCalliim  and  Fahyan  (cysts  in  the  neighborhood  of  the  superior 
parathyroids),  and  finally  three  cases  of  Schilder.  In  all  cases  exactly  in- 
vestigated up  to  the  present  these  cysts  have  been  found  at  the  site  of  the 
lateral  lobe  of  the  thyroid.  Dieterle  could  demonstrate  in  his  case  the 
absence  of  the  rudiments  of  the  superior  thyroid  arteries. 

We  are  therefore  justified  in  the  assumption  that  in  these  cases  an  anomaly 
of  formation  is  present  that  consists  in  an  agenesis  of  the  lateral  rudiments 
of  the  thyroid.  The  vesicles  found  at  their  site  consist  in  indifferent  rests 
of  the  postbranchial  bodies,  in  which  under  circumstances  isolated  thyroid 
follicles  may  be  imbedded.     At  the  root  of  the  tongue  are  found,  at  the  site 


SPORADIC    CRETIXISM  1 23 

of  the  median  rudiment  of  the  thyroid  gland,  analogous  indifferent  rests  wath 
traces  of  thyroid-gland  tissue,  which  not  infrequently  give  occasion  to  tumor 
formation.  The  cases  described  affect  children  who  have  reached  the  elev- 
enth year  of  Hfe  at  most.  The  girls  were  far  in  the  majority;  they  were  all 
weh  developed  at  birth.  Only  in  the  second  half  of  the  first  year  of  life 
did  there  gradually  occur  a  standstill  in  the  development.  Among  the 
numerous  cases  of  sporadic  cretinism  described  in  the  literature  a  large 
number  certainly  belong  to  thyroaplasia.  Diederle  counts,  among  others,  also 
the  two  cases  of  KocJier  and  the  known  case  of  Bourneville  {Pacha  de  Bicetre) . 
Also  two  cases  of  Magnus-Levy  belong  to  this  group.  The  above-mentioned 
case  of  Bourneville  attained  an  age  of  thirty-sLx  years.  As  I  have  said  be- 
fore, I  would  rather  not  take  up  the  question  whether  pure  cases  of  thyro- 
aplasia can  reach  so  old  an  age,  especially  if  they  have  not  been  previously 
treated.  In  any  case  it  is  established  that  also  in  complete  absence  of  the 
thyroid  gland,  life  and  a  certain  degree  of  development  is  possible. 

S3miptomatology.- — I  shall  now  describe  the  clinical  picture  of  sporadic 
cretinism  without  regard  to  the  etiology  of  special  cases.  We  must  in  every 
respect  consider  that  only  those  cases  which  show  the  fully  developed  clinical 
picture  can  belong  to  the  thyroaplastic  form,  while  in  the  incomplete  forms 
there  is  only  a  relative  insufficiency  of  the  thyroid  function  which  must  have 
begun  later  in  life. 

I  would  like  to  describe  three  cases  of  sporadic  cretinism  that  Herr  Hofrat 
Wagner  v.  Janeregg  kindly  allowed  me  to  examine. 

Observation  XJF.— ^Nlargerete  H.,  two  and  one-half  years.  Entered  the  psychiatric 
clinic  (of  Wagner)  Xov.  4,  1909.  Father  has  a  goiter,  avowedly  from  blowing  the  bugle- 
horn.  Otherwise  no  goiter  in  the  family.  Her  mother's  mother  was  insane.  Parents 
have  never  been  away  from  Menna.  A  five-year-old  child  of  the  parents  is  entirely 
normal.  The  birth  of  the  patient  was  normal;  she  was  nursed  by  the  mother  until 
the  end  of  the  second  year.  From  birth  lusty  and  lively;  large,  well  developed;  from 
the  eighth  month  on  the  parents  first  remarked  that  the  child  did  not  take  on  more 
weight  and  since  that  time  has  remained  at  a  standstill.  The  child  has  had  an  umbilical 
hernia  since  birth.      It  has  never  spoken. 

Height   62  cm. 

Circumference  of  skull,  42  cm. 

Breadth  of  shoulders,  45  cm. 

Circumference  of  breast,  45  cm. 

Pulse,  120. 

Rectal  temperature,  36°. 

Panniculus  adiposus  soft,  lax;  myxedematous  texture  of  the  skin;  walking  and  stand- 
ing impossible.  Forehead  arched  forward,  root  of  the  nose  somewhat  sunken  in;  no  teeth 
as  yet.  Eyelids  enormously  swollen,  tongue  thick,  abdomen  markedly  arched  forward; 
umbihcal  hernia.  Body  weight  7.1  kg.  From  Dec.  2,  1909,  on,  thyroidin  tablet  every 
third  day. 

Nov.  10,  1910. — 71  cm.  long,  weighs  9.1  kg.     Treatment  discontinued. 

Entrance  into  the  first  medical  clinic  on  Oct.  15.  Can  only  stand  when  it  holds  fast 
on  a  support,  cannot  speak,  is,  however,  otherwise  lively  and  busies  itself.  All  fontanelles 
closed. 


124 


THE    DISEASES    OF    THE    THYROID    GLAXD 


Circumference  of  skull,  46  cm. 
Circumference  of  breast,  50  cm. 
Circumference  of  abdomen.  48  cm. 
Anterior  superior  spine  to  internal  malleolus,  30  cm. 
Acromion  to  olecranon,  13  cm. 
Olecranon  to  stj'loid  process  of  radius,  12  cm. 
Skin  somewhat  dr>-,  no  distinct  my.xedema.     Root  of  nose  sunken  in  onh-  a  little. 
Tongue  always  protrudes  from  the  mouth;  left  anteriorly  below,  one  tooth  nucleus  pal- 


FiG.  12. — X-ray  picture  of  a  hand  of  a  sporadic  cretin  (Observation  XIV). 


pable,  otherwise  no  teeth.     Hearing  apparently  entirelj-  noynal.     ThjToid  gland  not 
palpable;  abdomen  distended,  hver  is  palpable,  indication  of  umbilical  hernia;  the  tickling 
reflexes  of  the  external  auditor^'  meatus  are  present.     Does  not  tell  when  she  wishes  to 
pass  feces  or  urine.     Xeryous  status,  as  far  as  elicited  by  tests,  normal. 
Patellar  reflexes  somewhat  liyely. 

Oct.  15. — 30  gm.  dextrose,  no  sugar. 

Noy.  II. — 50  gm.  dextrose,  no  sugar. 

Oct.  24. — Erythrocytes,  4,560,000. 


SPORADIC    CRETINISM 


125 


Leucocytes,  6800,  of  which: 
Polymorphonuclear  neutrophiles,  48.4  per  cent. 
Large  mononuclears,  8.3  per  cent. 
Lymphocytes,  40  per  cent. 
Eosinophiles,  ^.t,  per  cent. 
Nov.  II. — Erythrocytes,  5,250,000. 
Hb.,  55  per  cent. 
Leucocytes,  8200,  of  which: 
Polymorphonuclear  neutrophiles,  38  per  cent. 
Large  mononuclears,  37  per  cent. 
Lymphocytes,  54  per  cent. 
Eosinophiles,  4.3  per  cent. 
Nov.    26. — 0.0005    gni-    adrenalin    sub- 
cutaneously   and    50   gm.    dextrose   per   os. 
After  four  hours  3.2  per  cent,  sugar. 

Nov.  29. — One  drop  homatropine  in  eye; 
twenty-four  hours  later,  still  slight  mydriasis. 
Nov.    30. — Adrenalin,    0.0005    gm.,    no 
sugar. 

Nov.  20. — 0.005  g™--  pilocarpine  sub- 
cutaneously,  weak  sweat,  no  salivation. 

From  Dec.  2  on,  two  thyroidin  tablets 
daily;  from  6th  on,  three  daily;  from  8th  on, 
five  daily. 

Dec.  14. — Pulse  that  was  formerly  no, 
now  130;  thyroidin  medication  now  reduced 
to  one  tablet. 

Summary. — We  are  dealing  with  a  case  of 
sporadic  cretinism,  probably  depending  on  a 
congenital  aplasia  or  hypoplasia  of  the 
thyroid. 

Here  are  worthy  of  note  the  high  assim- 
ilation   boundary  for  sugar,   the  failure   of 

adrenalin  glycosuria,  the  strong  action  of  atropine  and  the  weak  action  of  pilocarpine; 
there  is,  however,  found  an  unusually  high  glycosuria  on  combination  of  dextrose  and 
adrenalin.     There  occurs  in  this  case  a  somewhat  high  tolerance  for  thyroidin. 

Rontgen  investigation  of  the  skeleton  of  the  hand,  Nov.,  1911:  The  bone-nuclei 
of  the  OS  magnum  and  the  unciform  bone  are  present.  Those  for  the  epiphysis  of  the 
radius  and  the  basal  epiphysis  are  still  absent.  The  skeleton  corresponds  to  that  of  a 
six-  to  eight-month-old  child  (Fig.  12). 

Sella  turcica  corresponding  to  the  size  of  the  skull. 

Observation  XV. — Franz  N.  (see  Fig.  13).  Entered  the  psychiatric  clinic  of  Wagner 
Oct.  6,  1909,  four  and  one-half  years  old,  from  Rudoletz  in  Mahren. 

The  fourth  child  of  healthy  parents.  Birth  easy,  at  the  right  time.  Head  at  birth 
already  large.  Speech  up  to  the  second  year  of  life  consisted  of  the  simplest  words 
only;  words  were  such  as  tata,  mamma,  and  since  this  time  the  child  has  not  spoken 
much  otherwise. 

Parents  and  the  entire  family  to  the  great-grandparents  of  the  child  have  not  suffered 
from  goiter.     Nowhere  in  the  neighborhood  does  the  father  know  of  a  similar  case. 

Length  of  body  85  cm.,  weight  19.2  kg.  Head  extremely  large  without,  however,  any 
hydrocephalic  formation.     Bones  of  the  head  of  hard  consistency.     Strong  development 


Fig.   13. — Sporadic  cretinism. 


126  THE    DISEASES    OF    THE    THYROID    GLAND 

of  the  skeleton  of  the  face.  Very  low  forehead,  eyes  stand  wide  apart.  Saddle-nose, 
epicanthus;  short,  very  broad  cartilaginous  nasal  framework;  cushiony  lips;  thick, 
broad  tongue,  that  protrudes  from  the  mouth.  Cushiony  ear  lobes  that  lie  close  to  the 
head.  Cheeks  very  thick,  throat  thick  and  stubby.  Thyroid  not  palpable.  Thick 
lanugo  hair  on  back.  Skin  of  the  body,  especially  in  the  supraclavicular  grooves  and 
on  the  backs  of  the  hands  and  feet,  springy,  elastic;  hands  and  fingers  chubby.  Abdomen 
much  distended.  Circumference  65I2  cm.  Reducible  umbilical  hernia.  Reflexes,  as 
far  as  can  be  tested,  present.     Noise  tests  were  without  any  reaction. 

From  June  23  on  was  given  one  thyroidin  tablet  daily,  until  Oct.  24.  Entrance  into 
the  first  medical  clinic.  Now  length  of  body  91.25  cm.,  weight  21  kg.  Treatment  is 
now  discontinued. 

Circumference  of  the  head  now  56  cm.,  circumference  of  the  abdomen  65  cm.,  cir- 
cumference of  breast  49  cm. 

Anterior  superior  spine  to  internal  malleolus  44.5  cm. 

Circumference  of  neck  36  cm. 

Heart  dullness  somewhat  broadened  (also  by  X-ray,  heart  of  characteristic  spherical 
shape).     Heart  sounds  pure. 

Border  of  the  liver  palpable  10  cm.  below  the  margin  of  the  ribs  in  the  mid-line, 
two  fingers'  breadth  below  in  the  right  mammillary  line. 

Umbilical  hernia  about  3  cm.  long,  and  its  insertion  2.5  cm.  in  diameter.  Penis  very 
small,  testicles  have  not  descended.  The  child  does  not  go  to  the  toilet  to  void  urine  or 
feces.  Slight  heightening  of  the  patellar  reflexes,  otherwise  the  reflexes  normal.  Nervous 
status,  so  far  as  can  be  tested,  normal. 

The  child  often  stares  into  space  for  a  long  time,  but  at  times  is  right  lively  and  cries 
loudly.  No  trace  of  speech.  Puts  all  objects  into  his  mouth,  even  his  own  feces.  Im- 
pressions of  hearing  entirely  absent,  no  reaction  of  the  eyelids  to  sounds. 

Nov.  2. — 50  gm.  dextrose  per  os,  no  sugar.  After  several  days  100  gm.  dextrose 
of  which  he  vomited  a  small  amount,  no  sugar  in  the  urine. 

Nov.  9. — Erythrocytes,  5,480,000. 
Hemoglobin,  70  per  cent. 
Leucocytes,  9000,  of  which: 
Polymorphonuclear  neutrophiles,  42.5  per  cent. 
Large  mononuclears,  8  per  cent. 
Lj^mphocytes,  41  per  cent. 
Eosinophiles,  8.5  per  cent. 

A  later  count  yielded: 

Erythrocytes,  5,400,000. 
Hemoglobin,  70  per  cent. 
Leucocytes,  11,000. 
Eosinophiles,  12  per  cent. 

Nov.  21. — o.oi  gm.  pilocarpine.     Sweat  extremely  slight,  salivation  negative. 

Nov.  22. — Homatropine  evinces  weak  mydriasis  only,  which  however  is  positive  after 
twenty-four  hours. 

Nov.  26. — o.ooi  gm.  adrenalin  subcutaneously  and  50  gm.  dextrose  per  os.  After 
four  hours  4.2  per  cent,  sugar. 

Nov.  29. — Weak  mydriasis  forty-eight  hours  after  installation  of  homatropine. 

Nov.  30. — o.ooi  gm.  adrenalin  subcutaneously,  no  sugar.  From  Dec.  2  on,  three  thy- 
roid tablets  a  day;  from  Dec.  5  on,  five  tablets  daily;  from  Dec.  8  on,  seven  tablets  daily. 

Dec.  13. — Marked  scaling  of  the  skin,  no  trace  of  moisture,  even  of  the  palms. 

Dec.  22. — Pulse  irregular,  only  72  to  the  minute,  although  frequent  abortive  beats. 


SPORADIC    CRETIXISil  1 27 

The  dose  was  reduced  to  three  tablets  and  after  some  days,  when  the  pulse  had  become 
entirely  regular  again,  five  tablets  were  given  continuously. 

Jan.  8. — ^Leucocytes,  4800,  of  which: 

PoljTuorphonuclear  neutrophiles,  61.5  per  cent. 
L}TiLphoc}'tes,  20.5  per  cent. 
Large  mononuclears,  12.5  per  cent. 
Eosinophiles.  5.5  per  cent. 

Jan.  19. — The  examination  of  the  hearing  now  shows  certainly  that  the  patient  reacts 
to  loud  noises.     Distinct  lid-reflexes. 

March  29. — Thyroidin  medication  has  now  been  continued  in  the  large  doses  without 
producing  manifestations  of  poisoning.  The  hearing  is  still  better,  the  enlargement  of 
the  liver  has  essentially  diminished  in  size;  otherwise  there  is  no  change. 

December,  1910. — The  nuclei  of  the  os  magnum  and  the  unciformbone  are  alone  visible 
in  the  carpus,  while  at  this  time  the  nuclei  of  the  entire  skeleton  of  the  carpus  shoiold 
have  been  laid  down.  The  epiphysis  of  the  radius  is  present.  The  skeleton  corresponds 
to  that  of  a  one  and  one-half  to  two-year  child. 

Summary. — The  patient  is  from  a  goiter-free  neighborhood.  There  exist  no  other 
grounds  for  the  assumption  of  an  endemic  cretinism.  We  are  indeed  dealing  with  sporadic 
cretinism,  probably  dependent  on  aplasia  or  high-grade  hj^Doplasia  of  the  thjToid  gland; 
and  perhaps  later  there  was  added  some  other  factor  that  we  are  not  able  to  define  that 
made  the  insufficiency  still  greater. 

Thyroid  medication  here  succeeded  less  than  in  the  preceding  case.  It  was  also 
introduced  much  later.     Apparently  the  thyroid  insufficiency  is  here  ver\-  much  greater. 

The  investigation  with  adrenahn  and  pilocarpine  several  weeks  after  the  discon- 
tinuation of  thjToid-gland  therapy  shows  slight  or  negative  action.  The  test  as  to  ali- 
mentar>^  glycosuria  results  negative.  It  is  verj-  interesting  also  that  in  this  case  adrenalin 
plus  dextrose  leads  to  an  entirely  usual  degree  of  glycosuria. 

Worthy  of  note  in  this  case  is  the  enormous  tolerance  for  thyroidin  and  also  the 
action  of  thyroidin  on  the  disturbance  of  hearing  and  on  the  enlargement  of  the  liver. 

Observation  XVI. — H.  A.,  entrance  into  the  psychiatric  clinic  (of  Wagner)  Jan.  21, 
1909.  Fifteen  years  old,  female  dwarf  (95  cm.);  face  puffy,  skin  of  the  entire  body  myxe- 
dematous, dry  and  scaly.  Supracla^dcular  fossse  filled  with  pad-like  masses.  Con- 
junctivitis eczematosa.  Fundus  normal.  Circumference  of  skuU  50I2  cm.  Root  of 
nose  sunken,  tongue  thick,  also  the  lips;- the  teeth  with  transverse  ridges,  in  great  part 
carious,  have  remained  verj"  much  behind  in.  their  development.  Abdomen  marked!}' 
distended,  umbilical  hernia. 

Measurements. — Height.  95  cm. 
Circumference  of  skull.  50I2  cm. 
L'pper  arm  (acromion  to  olecranon^  19  cm. 
Arm  proper,  13  cm. 
Lower  extremity  (spine  [anterior  superior]  to  heel).  46  cm. 

InteUigence  that  of  a  four-year  child.  Can  speak,  can  understand  questions  and  state- 
ments addressed  to  her;  can,  however,  not  w-rite  nor  read,  and  can  say,  of  a  prayer,  only 
the  words  at  the  beginning.     Weight  20  gm. 

From  April  27  on,  0.5  gm.  sodium  iodide,  after  which  she  became  livelier;  from  June 
8  on,  one  thyroid-gland  tablet  a  day.  Body  weight  at  the  beginning  of  July  had  gained 
16.9  kg.  The  bowel  movements,  which  formerly  frequently  occurred  only  everj'  two  or 
three  days,  have  gradually  become  entirely  normal.  Rapid  mental  development.  Is 
much  more  active,  plaj-s  much,  wants  a  looking  glass,  a  net  for  her  hair,  begins  to  sing. 

Jan.  18,  1910. — loi  cm.  ]\I}-xedematous  texture  of  the  skin  much  lessened,  slight 
sweating  of  the  palms  of  the  hands.     Dermographism. 


128 


THE    DISEASES    OF    THE    THYROID    GLAND 


Oct.  13,  1910. — The  patient,  sixteen  and  three-fourths  years  old,  now  enters  the 
medical  clinic.  Length  no  cm.,  weight  23  kg.  The  thyroid-gland  medication  is  now 
discontinued.     Circumference  of  the  skull  571^  cm. 

Hair  soft,  skin  somewhat  dry,  only  the  palms  of  the  hands  moist,  tongue  not  enlarged, 
teeth  much  behind  in  their  development.     Circumference  of  abdomen  62  cm.;  there  still 


Fig.  14. 


Fig.  i^ 


Sporadic  cretinism. 


remain  indications  of  an  umbilical  hernia.  Liver  palpable  two  fingers'  breadth  below 
the  margin  of  the  ribs.  Pubis  and  axillae  entirely  devoid  of  hair.  External  genitalia 
hypoplastic.  Has  never  menstruated.  The  entire  trachea  is  distinctly  palpable,  there 
is  nothing  to  be  felt  of  the  thyroid.  She  gives  correct  information  as  to  where  she  has 
been  the  last  year.  Cannot  reckon,  counting  impossible. 
Oct.  15. — 100  gm.  dextrose,  weakly  positive. 


SPORADIC    CRETINISM 


129 


Erythrocytes,  4,540,000. 
Leucocytes,  11,200,  of  which: 
Lymphocytes,  49  per  cent. 
Large  mononuclears,  9.5  per  cent. 
Lymphocytes,  51.0  per  cent. 
Eosinophiles,  7  per  cent. 

Oct.  25. — ICO  gm.  dextrose,  no  sugar. 

Nov.  I. — Hands  feel  cool  to  the  touch;  patient  has  gained  1.7  kg.  since  her  entrance. 


Fig.  16. — Sporadic  cretinism,  seventeen-year-old  girl.  In  spite  of  a  long-continued  thyroid 
treatment  the  development  of  the  skeleton  of  the  hand  is  that  of  a  normal  girl  aged  ten  years 
(see  Fig.  17). 

Nov.  3. — ^Leucocytes,  12,100,  of  which: 
Polymorphonuclear  neutrophiles,  40.6  per  cent. 
Large  mononuclears,  4.6  per  cent. 
Lymphocytes,  49  per  cent. 
Eosinophiles,  5.8  per  cent. 

Nov.  9. — ^Leucocytes,  11,500. 
Hemoglobin,  65  per  cent. 
9 


130  THE    DISEASES    OF    THE    THYROID    GLAND 

Nov.  10. — -150  gm.  dextrose,  no  sugar. 

Nov.  16. — Skin  entirely  dry.     o.oi  gm.  pilocarpine;  no  salivation,  only  slight  sweating. 

Nov.  19. — Nervous  status.  Superficial  abdominal  reflexes  increased  and  also  plantar 
reflex  lively;  otherwise  normal,  as  far  as  can  be  investigated. 

Only  very  slight  mydriasis  after  homatropine.  On  Nov.  22,  o.ooi  gm.  adrenaHn 
subcutaneously  and  100  gm.  grape-sugar  by  mouth.  Minimal  increase  in  blood-pressure, 
lasting  only  for  a  very  short  time.  Pulse  only  84  to  92.  In  the  first  two-hour  period,  no 
sugar;  in  the  second,  4.25  per  cent,  in  15  cc.  urine;  in  the  next  twelve-hour  period,  Trommer 
still  strongly  positive. 

Nov.  26. — O.OOI  gm.  adrenalin,  no  sugar. 

Nov.  29. — Circumference  of  skull,  563^2  cm.,  total  height,  in  cm.  Circumference  of 
abdomen,  62  cm.,  circumference  of  breast  (mammillae),  64  cm.,  circumference  of  neck,  28 
cm.  Upper  arm  (acromion  to  olecranon),  21.5  cm.,  arm  proper,  18.5  cm.,  lower  extremity 
([anterior  superior]  spine  to  heel),  52  cm. 

Dec.  2. — Up  to  this  time,  pulse  between  100  and  no.  Bowel  movements  not  entirely 
regular,  in  that  one  bowel  movement  is  wanting  every  three  to  five  days.  From  now  on, 
five  thyroidin  tablets  a  day.  From  Dec.  6  on,  seven  tablets  a  day.  Dec.  8,  nine  tablets 
a  day. 

During  the  next  days  the  pulse  rises  up  to  145  and  sinks  to  its  former  count  only  on 
Dec.  22. 

Leucocytes:   10,200,  of  which: 
Polymorphonuclear  neutrophiles,  67.2  per  cent. 
Large  mononuclears,  8.2  per  cent. 
Lymphocytes,  22.6  per  cent. 
Eosinophiles,  2  per  cent. 

X-ray  examination  of  the  hand  skeleton.  The  epiphysial  junctures  of  the  fingers 
and  metacarpal  bones  are  still  open.  The  skeleton  of  the  carpus  is  as  yet  laid  out  in  the 
form  of  round  bone-nuclei.  At  this  age  the  carpal  bones  should  be  fully  developed, 
and  the  epiphysial  junctures  should  be  closing  up  (Fig.  16).  Sella  turcica  corresponding 
to  the  size  of  the  skull. 

Summary. — Sporadic  cretinism  probably  due  to  aplasia  or  high-grade  hypoplasia  of 
the  thyroid  gland.  The  thyroid-gland  therapy  instituted  in  the  sixteenth  year  is  able  to 
affect  the  growth  not  inappreciably  and  to  further  intellectual  development.  We  may 
readily  comprehend  that  the  marked  inhibition  of  development  that  has  existed  for 
sixteen  years  cannot  entirely  be  done  away  with. 

The  investigation  of  the  carbohydrate  metabolism  showed  that  after  the  year-long 
administration  of  thyroidin  the  assimilation  limits  for  grape-sugar  lay  abnormally  low. 
It  is  very  instructive  that  with  the  discontinuation  of  the  thyroid  medication  the  assimila- 
tion limits  rose  immediately,  so  that  after  several  weeks  as  much  as  150  gm.  dextrose 
would  be  borne.  Also  adrenalin  produces  no  glycosuria,  while,  on  the  contrary,  adrenalin 
and  grape-sugar  produce  abundant  glycosuria. 

An  over-loading  test  with  thyroidin  showed  that  the  tolerance  in  this  case  was  at 
any  rate  rather  high,  as  symptoms  of  poisoning  first  occurred  only  with  large  doses. 
Under  the  test  with  thyroidin,  the  number  of  neutrophiles  rose  considerably,  and  the 
assimilation  limits  for  grape-sugar  again  sank  rapidly. 

In  the  clinical  picture  of  sporadic  cretinism  the  phenomenon  most  be- 
fore the  eyes  is  the  disturbance  in  growth.  Buschan  collects  from  the  litera- 
ture thirty-four  cases  of  sporadic  cretinism  that  showed  evident  dwarf- 
ism.    In  the  cases  with  high-grade  disturbance  of  the  function  of  the  thyroid 


SPORADIC    CRETIXISM 


131 


gland  the  length  of  the  body  was  mostly  below  i  meter.  Siegert  describes 
a  two-and-a-half-year-old  child  of  50  cm.  length;  v.  Eiselsherg  a  thirteen-year- 
old  girl  of  80  cm.  length.  In  addition  to  the  disturbance  in  the  growth  in 
height  are  found  delay  in  the  appearance  of  the  bone-nuclei,  and  in  the  clo- 


FiG.  17. — X-ray  picture  of  the  hand  of  a  normal  ten-j-ear-old  girl. 

sures  of  the  epiphyses  (Hertoghe.  v.  Wyss,  Kassouitz,  Diderle,  Siegeri,  and 
others).  The  original  statement  of  VircJio-ii'  that  the  calcification  appears 
prematurely  was  later  found    to    be  incorrect;    the  case  investigated   by 


132  THE    DISEASES    OF    THE    THYROID    GLAND 

Virchow  was  one  of  chondrodystrophy  (Kaufmann).  This  was  further 
confirmed  by  Weygandt  through  the  microscopical  examination  of  Vircliow^s 
case. 

Already  Argutinsky  had  mentioned  that  the  development  of  the  bone- 
nuclei  in  sporadic  cretinism  is  even  more  intensely  delayed  than  is  the  growth 
in  height.  If,  for  example,  the  size  of  a  twenty-year-old  cretin  corresponds 
to  that  of  a  six-year-old  child,  the  retardation  in  the  deposition  of  the  nuclei 
lies  even  farther  behind.  In  the  pure  cases  with  complete  lack  of  thyroid 
gland  the  epiphysial  joints  do  not  close.  In  the  known  case  of  Bour?ieville, 
autopsy,  in  the  thirty-sixth  year  of  age,  showed  epiphyses  that  were  com- 
pletely open.  The  closure  of  the  fontanelles  is  markedly  delayed.  In 
the  case  mentioned  the  great  fontanelle  was  still  open  in  the  twentieth 
year.  At  autopsy  in  the  thirty-sixth  year  its  place  was  filled  by  a  trans- 
lucent bony  plate.  Also  Kassowitz  mentions  cases  of  infantile  myxe- 
dema with  markedly  delayed  closure  of  the  fontanelles;  thus  in  a  thirteen- 
year-old  individual  he  found  the  frontal  fontanelles  still  distinctly  open. 
The  measurements  of  the  bones,  with  regard  to  their  thickness  and  length, 
correspond  to  the  relations  of  childhood ;  this  is  then  a  proportional  dwarfism, 
deviating  from  the  normal  proportions  of  childhood  only  in  the  development 
of  the  skull.  The  circumference  of  the  skull  does  not  indeed  correspond 
to  the  age  of  the  individual,  but  is  distinctly  larger  than  would  be  repre- 
sented by  the  rest  of  the  body  structure.  In  addition  there  is  a  remaining 
behind  in  the  growth  of  the  vomer,  that  results  in  a  retraction  of  the  root  of  the 
nose;  this  lends  to  the  face  the  characteristic  cretinoid  expression,  which 
does  not,  however,  reach  the  extreme  grade  as  seen  in  chondrodystrophy.  In 
the  four-month-old  case,  with  pure  thyroaplasia,  of  Dieterle,  the  measure- 
ments of  the  bones  showed  that  they  about  corresponded  to  those  of  a  new- 
born child.  The  disturbance  in  growth  had  therefore  apparently  first  made 
its  appearance  after  birth,  and  not  already  in  fetal  life.  The  histological 
examination  of  the  bones  in  sporadic  cretinism  showed  diminution  in  the  size 
of  the  zone  of  cartilage  proliferation,  narrowing  of  the  marrow  cavity,  abun- 
dant fat-contents  of  the  marrow,  and  poverty  of  the  marrow  spaces  in  cells. 
According  to  Dieterle  there  also  occurs  a  slowing  of  apposition  and  absorption, 
with  normal  calcification.  This  gives  rise  to  a  certain  degree  of  sclerosis. 
With  this  agrees  the  observation  of  Kassoicitz  and  of  Dieterle  that  the  bones, 
when  once  formed,  show  an  unusual  hardness,  thus  differing  from  their 
condition  in  rachitis.  The  histological  picture  of  the  bones  shows  a  cer- 
tain senility;  the  disturbance  depends  on  an  equalized  delay  of  the  endo- 
chondral and  periosteal  ossification. 

It  is  further  characteristic  for  the  disturbance  in  growth  in  sporadic 
cretinism  that  it  reacts  to  thyroid  therapy  in  a  pronounced  manner,  even 
when  the  therapy  is  first  begun  after  the  twentieth  year.  We  shall  speak  of 
this  in  the  consideration  of  the  therapy. 


SPORADIC    CRETINISM  I33 

In  the  incomplete  forms  of  sporadic  cretinism  the  disturbances  of  growth 
are  characterized  by  their  shghter  intensity.  Here  closure  of  the  epiphysial 
junctures  may  occur,  even  in  advanced  years.  I  mention  as  example  a 
case  of  Magnus-Levy,  in  which  the  treatment,  instituted  in  the  forty-fifth 
year — the  patient  was  132  cm.  tall — failed  to  exercise  any  influence  on 
growth,  as  the  epiphysial  junctures  were  already  fully  ossified. 

Disturbances  in  dentition  go  hand-in-hand  with  those  of  growth  of  the 
bones.  When  the  thyroid  gland  is  entirely  absent  the  children  during  the 
first  year  remain  completely  toothless.  In  the  later  years  the  milk-teeth 
develop  very  slowly  and  finally  remain  partially  retained.  (Often  in  addition 
to  the  retained  milk-teeth  are  found  the  rudiments  of  the  permanent  teeth.) 
Here  thyroid  therapy,  as  we  shall  see  later,  may  elicit  excellent  results. 

Umhilical  hernia  is  a  constant  finding  in  the  higher  grades  of  sporadic 
cretinism.  Kassowitz  observed  it  sixteen  times  in  twenty-two  cases  of 
infantile  myxedema.  The  eldest  of  these  children  was  twelve  years  old. 
The  hernia  may  attain  the  size  of  an  apple.  Therewith  the  'abdomen  is 
distended,  the  navel  is  markedly  deep  (Argutnisky) ,  there  is  high-grade 
obstipation,  which  in  the  case  of  Maresch  led  to  prolapse  of  the  rectum.  The 
myxedematous  texture  of  the  skin  is  for  the  most  part  distinctly  evident;  in 
the  older  cases,  however,  the  skin  is  on  the  other  hand  rather  atrophic,  only  the 
pad-like  swellings  of  the  supraclavicular  grooves  and  the  slight  puffiness  of 
the  face,  especially  the  eyeUds,  remain.  For  the  most  part  the  limit  of  the 
hair  zone  is  far  back  on  the  forehead,  to  which  are  added  protuberance  of  the 
malar  bones,  retraction  of  the  root  of  the  nose,  cushiony  lips,  protrusion  of 
enlarged  tongue;  all  this  lends  the  impression  of  something  of  an  animal 
appearance  to  the  face. 

Inspection  of  the  mouth  shows  that  the  palatine  arches  are  for  the  most 
part  high,  deepened  with  furrows,  the  tonsils  enlarged;  and  often  in  the 
pharyngeal  space  there  are  adenoids.  The  hypertrophic  rhinitis  which  is 
present  disturbs  breathing;  the  children  snufiie  and  snore;  in  most  cases 
there  is  a  discharge  from  the  nose.  In  two  of  the  above  cases  I  found  a 
distinct  enlargement  of  the  liver.  In  the  case  of  Argutinsky  there  is  the  state- 
ment that  the  border  of  the  liver  was  palpable  two  and  one-half  finger- 
breadths  below  the  margin  of  the  ribs. 

It  should  also  be  mentioned  that  in  the  fully  developed  cases,  the  breath- 
ing is  extraordinarily  slowed.  K  twenty-eight-year-old  case  of  Magnus- 
Levy^s,  who  at  the  age  of  fourteen  years  had  sustained  a  total  strumectomy, 
breathed  only  six  times  in  the  minute. 

The  sweat-inducing  action  of  pilocarpine,  in  the  three  cases  cited,  was  very 
slight;  salivation  failed  entirely;  the  mydriatic  action  of  homatropine  lasted 
very  long. 

The  developmental  disturbances  of  the  genitalia  are  always  very  marked. 
In  females  the  labia  majora  are  stunted  and  do  not  cover  the  labia  minora; 


134  THE    DISEASES    OF    THE    THYROID    GLAND 

uterus  and  ovaries  are  highly  hypoplastic  and  the  breasts  fail  to  develop. 
In  males  the  penis  is  very  small,  the  testicles  do  not  descend  at  all  or  descend 
very  late,  and  in  many  cases  are  essentially  smaller  than  in  the  normal  indi- 
vidual. The  pubic  and  axillary  hair  does  not  develop.  With  the  failure  of 
sexual  maturity  in  boys,  there  occurs  also  the  failure  of  the  change  of  voice. 

The  hematopoietic  system  also  suffers  in  development.  The  hemoglobin 
contents  is  for  the  most  part  much  reduced,  more  than  the  number  of  erythro- 
cytes. This  behavior  was  very  well  illustrated  in  the  three  cases  described 
although  all  three  had  been  treated  for  a  long  time  with  thyroid  tablets.  For 
the  most  part  the  number  of  leucocytes  is  increased.  The  differential  count 
of  these  shows  an  enormous  reduction  in  the  polymorphonuclear  neutrophiles 
and  a  corresponding  increase  of  the  mononuclear  cells,  even  when  we  con- 
sider that  in  children  the  number  of  neutrophile  cells  is  smaller  than  in  adults. 
The  leucocytic  picture  shows  the  type  of  earlier  stages  of  development 
{Meunacher).  Among  the  mononuclear  cells  are  found  a  great  number  of 
granular  cells.     Also  Turk's  irritation  forms  are  observed  (Esser). 

The  number  of  eosinophile  cells  is  mostly  very  much  increased.  In  my 
three  cases  the  percentage  was  12  to  33. 

Thus  the  blood  findings  behave  similarly  to  those  of  adult  myxedemics, 
only  the  deviations  from  the  normal  are  more  strongly  expressed.  Also  the 
pathologico-anatomical  findings  agree  with  this.  While  thyroidectomy  in 
adult  animals  does  not  lead  to  a  distinct  alteration  of  the  bone  marrow,  there 
has  been  observed  by  Kraus  in  young  animals  after  thyroidectomy  a  lym- 
phoid metamorphosis  of  the  bone  marrow;  also  Aschoff  found  in  his  case  of 
thyroaplasia  a  lymphoid  metaplasia  of  the  marrow  of  the  femur. 

In  sporadic  cretinism,  as  in  myxedema  adultorum,  there  is  found  a  para- 
doxical action  of  the  thyroid  substance  on  the  leucocytic  formula.  While 
the  administration  of  thyroid-gland  substance  in  normal  individuals  increases 
the  count  of  mononuclears  at  the  cost  of  polymorphonuclear  neutrophiles, 
we  find  in  conditions  of  hypothyrosis  under  thyroid  medication,  together 
with  the  increase  in  hemoglobin  and  the  number  of  red  cells,  also  an  increase 
in  neutrophile  cells,  with  a  decrease  in  mononuclears.  The  abnormal  forms 
vanish  from  the  blood  and  the  leucocytic  formula  approaches  its  normal 
constitution.  In  a  case  of  juvenile  myxedema  (complicated  with  symptoms 
of  deficiency  on  the  part  of  the  other  ductless  gland),  I  observed  that  the 
count  of  neutrophiles  increased  from  54  per  cent,  to  84  per  cent,  during  a 
two  months'  thyroid  treatment. 

Esser  saw  in  a  myxedemic  child  the  count  of  neutrophiles  increase  under 
thyroid  treatment  from  19  per  cent,  to  41  per  cent.;  later,  intoxication  symp- 
toms developed  and  with  these  the  count  of  neutrophiles  again  sank  to  19 
per  cent.  I  oft'ered  in  explanation  of  this  case,  that  at  first  the  thyroid 
medication  exercised  its  usual  favorable  influence  on  the  blood  picture  of 
hypothyrosis,  but  that  later  with  the  appearance  of  the  intoxication  symptom 
it  assumed  the  character  of  hyperthyrosis. 


SPORADIC    CRETINISM 


135 


In  case  N.,  Observation  XV  (sporadic  cretinism),  the  neutrophilic  count 
rose  from  42.5  per  cent.  (Nov.  9)  to  61.5  per  cent.  (Jan.  18);  in  case  A.,  Ob- 
servation XVI,  from  32.5  per  cent.  (Oct.  15)  to  67.2  per  cent.  (Dec.  22),  under 
treatment  with  large  doses  of  thyroidin. 

Summarizing  these  observations,  it  may  be  said  that  on  the  absence  or 
insufficient  production  of  thyroid  extract  in  the  juvenile  organism,  the  devel- 
opment of  the  hematopoietic  system  is  severely  inhibited.  Agreeing  with 
this  is  Diederle's  observation  that  the  disturbance  in  the  growth  of  bone 
does  not  he  in  the  marrow  of  the  epiphysial  cartilage  alone,  but  also  in  the 
bone  marrow  itself.  Especially  does  the  development  of  the  neutrophilic 
cells  suffer  damage.  There  exists  a  shght  grade  of  status  lymphaticus  that 
perhaps  is  in  relationship  with  the  faulty  development  of  the  chromaffin 
tissue. 

The  metabolism  of  sporadic  cretinism  has  been  carefully  studied  in  the 
excellent  investigation  of  Magnus-Levy.  I  reproduce  from  the  table  of  this 
author  the  following  figures: 


Age, 
years 

Length, 
cm. 

Weight, 
kg. 

Cc, 
O2 

Cc, 
CO2 

Cc,  O2 
per  kg. 

Relation  of  the  O2  excre- 
tion to  that  of  a  healthy 
individual 

Case     I 

29 

98.0 

21.  I 

77-5 

S4-S 

3-67 

48  per  cent. 

Case   11 

14 

84.0 

15-8 

72.6 

59-4 

4.62 

60  per  cent. 

Case  III 

46 

132.0 

42. 5 

122.4 

104.9 

2.88 

5S  per  cent. 

Case    V 

14 

131-5 

29-5 

IS4-I 

137.0 

5.22 

96  per  cent. 

(light) 

In  the  fully  developed  form,  the  fundamental  exchange  is  therefore  much 
reduced. 

With  this  agrees  the  experiment  of  v.  Bergmann.  He  investigated  the  met- 
abolism of  a  one-year-old  child,  employing  the  Voit-Pettenkofer  apparatus. 
The  child  was  put  in  equilibrium  with  a  supply  of  calories  that  was  far  below 
that  needed  for  a  healthy  child  of  like  weight.  Concerning  the  albuminous 
metabolism,  I  shall  refer  to  the  chapter  on  myxedema  adultorum.  The  salt 
metabolism  in  infantile  myxedema  is  dealt  with  in  investigations  of  Haugardy 
and  Langstein.  These  authors  found  that  in  their  case  the  assimilation  of 
calcium  amounted  to  about  one-third  of  that  of  a  normal  child  the  same  age. 
In  this  the  intensity  of  the  inhibition  of  bone  growth  finds  expression  in  a 
pretty  manner. 

As  concerns  the  carbohydrate  metabolism,  I  might  mention  that  in  the 
three  cases  of  sporadic  cretinism  that  we  investigated  the  assimilation  limits 
for  carbohydrates  lay  rather  high  several  weeks  after  the  withdrawal  of  thyroid 
medication.  Also  injection  of  adrenalin  did  not  lend  to  glycosuria,  while  on 
the  contrary  injection  of  adrenalin  with  simultaneous  administration  of  sugar 
always  yielded  strikingly  high  sugar  percentages  in  the  urine.  Perhaps  we 
may  seek  the  cause  of  this  in  the  fact  that  in  sporadic  cretinism  also  the  de- 


136  THE    DISEASES    OF    THE    THYROID    GLAND 

velopment  of  the  other  ductless  glands  suffer  damage  on  account  of  the 
disturbances  appearing  in  early  youth,  so  that  the  simultaneous  overburden- 
ing of  the  alimentary  and  the  nervous  factors  bring  about  an  appreciable 
insufificiency. 

The  reduction  of  the  metabolic  processes  expresses  itself,  here  as  in 
myxedema  adultorum,  in  a  hypothermia.  For  the  most  part  the  temperatures 
lie  near  36°;  also  in  my  cases,  the  level  of  temperature  was  low. 

In  his  case  Diederle  found  during  the  last  week  of  the  life  of  the  patient 
33.4°.  Then  again  an  increase  of  temperature  may  remain  absent  when 
infectious  processes  occur.  However,  this  is  not  usually  the  case.  Jn  the 
case  of  Bourneville,  already  mentioned  many  times,  the  temperature  during 
a  case  of  erysipelas  rose  to  40°  Celsius. 

The  statements  as  to  the  behavior  of  the  hypophysis  in  sporadic  cretinism 
do  not  agree.  Extirpation  of  the  thyroid  gland  in  young  rabbits  leads  to 
enlargement  of  the  hypophysis  (Rogon'itsch,  Gley,  and  others).  Microscopical 
alterations  of  an  apparently  degenerative  nature  have  been  many  times 
described.  Again,  in  many  cases  of  sporadic  cretinism  the  hypophysis  or 
the  sella  turcica  is  enlarged.  In  my  case,  however,  the  X-ray  examination  of 
the  skull  showed  no  enlargement  of  the  sella.  Schilder  likewise  found  in  his 
three  cases  of  thyroaplasia  no  enlargement  of  the  sella;  but  on  microscopical 
examination  he  found  peculiar  cells  that  approached  near  to  the  so-called 
'^ pregnancy  cells"  of  the  hypophysis. 

In  sporadic  cretinism  the  thymus  gland  often  seems  hypoplastic;  Pineles 
found  thyroaplasia  and  thymus  aplasia  combined.  Bernheim-Karrer  and 
Rucacz-Gruchet  found  only  slight  rests  of  the  thymus.  Other  observers 
found  the  thymus  normally  developed. 

The  marked  inhibition  in  the  development  of  the  osseous  and  the  blood 
systems  and  the  ductless  glandular  system  would  lead  us  to  expect  that  there 
would  also  be  something  wanting  in  the  development  of  the  central  nervous 
system.  This  in  the  high-grade  cases  expresses  itself  not  only  in  the  absence 
or  remaining  backward  of  the  mental  and  psychical  development,  but  even 
in  the  inabiUty  to  carry  out  the  movements  that  subserve  finer  coordination. 
As  Kasson'itz  observes,  the  children  learn  late  to  balance  their  heads,  to  sit, 
and  to  walk. 

Such  cases,  as  for  instance  the  case  of  N.  described  (Observation  XV), 
have  almost  nothing  human  left  about  them.  They  give  utterance  to  only 
some  inarticulate  sounds  and  almost  every  sign  of  mentality  is  absent. 
They  do  not  go  to  the  toilet  to  void  urine  or  feces.  X.  always  devoured  his 
feces  whenever  he  could  get  access  to  them.  In  lighter  cases  the  disturbance 
of  mental  development  is  somewhat  shorter.  Usually  the  sense  of  smell  is 
well  developed. 

The  statements  as  to  disturbances  of  hearing  in  sporadic  cretinism  are  very 
diverse.     The  assumptions  as  to  the  cause  of  these  diverge  greatly.     It  is 


SPORADIC    CRETINISM  137 

certain  that  the  absence  or  insufficiency  to  the  function  of  the  thyroid  may 
lead  to  disturbances  of  hearing.  I  refer  to  the  results  of  thyroid  medica- 
tion that  are  often  attained  in  a  striking  manner  in  these  cases.  It  is  just  as 
certain,  however,  that  with  complete  failure  of  the  thyroid  gland  the  organ  of 
hearing  may  be  completely  developed  from  birth  on.  Siehermann  examined 
the  organ  of  hearing  in  Dieterle's  cases  of  congenital  thyroaplasia  and  found 
entirely  normal  relationships  in  an  anatomical  sense.  Even  in  a  functional 
sense,  disturbances  do  not  necessarily  have  to  be  present — for  Maresch's 
case  of  thyroaplasia  showed  no  deafness.  Hence  what  is  under  dispute  is 
only  how  to  explain  the  disturbances  that  occur  in  many  cases,  v.  Wagner 
was  the  first  to  express  the  opinion  that  myxedematous  swelling  of  the 
mucous  membrane  of  the  tympanum,  the  Eustachian  tube,  etc.,  could  fur- 
nish the  cause  of  the  hardness  of  hearing.  On  the  contrary,  Denker  states  that 
thyroidectomized  animals  after  operation  are  completely  deaf,  show  as  the 
result  of  histological  examination  no  myxedematous  alterations  of  the 
mucous  membrane  and  the  organ  of  hearing,  nor  any  degenerative  alterations 
in  the  nervous  organ  of  hearing  or  in  the  bulbar  centers.  The  hypothesis  of 
a  dysthyric  hardness  of  hearing  {Block)  is  therefore  denied.  It  is  feasible 
to  think,  as  many  otologists  assume,  that  central  perception  of  the  stimulus 
of  sound  suffers.  There  is  then  concerned  a  form  of  cortical  deafness,  or  that 
form  of  deafness  which  Heller  describes  as  psychical  deafness,  in  which  the 
perception  of  words  does  not  come  to  consciousness,  or  as  Gutzmann  suggests, 
serious  defects  of  attention  or  a  high-grade  weakness  of  memory  for  speech 
make  their  perception  of  words  entirely  impossible.  Not  entirely  easy  is 
differential  diagnosis  from  sensory  aphasia.  The  distinction  is  made  possible 
only  by  the  characteristic  signs  of  feeble-mindedness.  One  of  my  cases 
(case  N.)  seemed  to  be  deaf-and-dumb.  This  was  striking  as  otherwise 
complete  hearing  mutism  [Horstummheit]  does  not  seem  to  occur  in  sporadic 
cretinism.  The  ear  tickling  reflex  was  present.  From  the  side  of  the  spec- 
ialists, hearing  mutism  [Horstummheit]  was  supposed  to  be  present  {Dr. 
Frbschels).  The  conception  of  hearing  mutism  is  not,  however,  uniform 
among  otologists.  Gutzmann,  Nadoleczny,  H.  Stern  and  others  speak  of  hear- 
ing mutism  only  when  it  concerns  individuals  (mostly  children  from  third 
to  seventh  year)  who  are  mute  in  spite  of  intact  intelligence  and  intact 
hearing.  These  cases  of  pure  hearing  mutism  are  not  common.  In  the  case 
of  N.  there  indeed  occurred,  after  several  months'  treatment  with  large  doses 
of  thyroidin  (to  seven  tablets  a  day),  a  slight,  but  distinct,  degree  of  abihty 
to  hear  (lid  reflex).  Unclear  however  remains  the  circumstance  that  also  in 
complete  absence  of  thyroid  gland  from  birth,  deafness  does  not  always  de- 
velop; as  has  already  been  mentioned,  there  occur  cases  of  thyroaplasia  that 
heard.  Also  I  should  not  neglect  to  mention  that  in  the  numerous  dogs  on 
which  I  myself  performed  thyroidectomy,  and  on  which  later  exact  investi- 
gation disproved  any  existence  of  accessory  thyroids,  there  were  never  to  be 


138  THE    DISEASES    OF    THE    THYEOID    GLAXD 

observed  perceptible  mutism  even  after  a  period  of  observation  lasting  up 
to  two  years.     The  question  still  needs  careful  study. 

In  cases  in  which  the  power  of  hearing  is  markedly  affected  or  is  absent,  the 
development  of  speech  is  of  course  also  slight;  in  the  case  mentioned,  case  X., 
it  was  limited  to  a  few  inarticulate  sounds. 

We  know  nothing  as  to  the  etiology  of  thyroaplasia  and  thyrohypoplasia. 
Pineles  states  that  there  are  sometimes  malformations,  tuberculosis,  or  alco- 
holism in  the  ancestry,  but  this  statement  does  not  explain  much.  For  in- 
fantile myxedema,  all  those  damaging  influences  come  into  consideration  that 
were  set  forth  for  myxedema  adultorum.  Worthy  of  note  is  the  statement  of 
Spolverini,  that  sucklings  who  were  nursed  by  w^omen  with  goiter  developed 
myxedema.  All  of  Spolverini' s  observations,  however,  do  not  seem  to  me  to  be 
free  from  objection.  It  seems  well  in  this  case  for  us  to  assume  an  expectant 
attitude,  until  more  observations  have  been  made.  The  thyroid  secretion 
does  not  seem  to  go  over  in  the  milk,  as  according  to  many  observations 
[Lange  and  others)  it  was  found  that  sucklings  who  were  nursed  by  healthy 
women,  might  yet  develop  myxedema. 

Differential  Diagnosis. — In  the  diagnosis  of  infantile  myxedema  all  those 
points  are  to  be  considered  that  were  mentioned  in  the  diagnosis  of  myxedema 
adultorum.  To  these  are  added  in  infantile  myxedema  the  ear  marks  of  the 
remaining  behind  in  the  physical  and  the  mental  development.  Among 
these  the  inhibition  of  ossification  is  especially  important.  Siegert  is  justified 
in  emphasizing  this.  One  should  not  forget,  however,  that  in  many  vegetative 
disturbances,  that  have  nothing  to  do  with  the  thyroid  gland,  a  delay  in 
ossification  may  exist.  As  far  as  it  affects  only  the  closure  of  the  epiphyses, 
as  for  instance  in  the  case  in  eunuchoidism,  it  offers  no  difficulty  from  the 
standpoint  of  dift"erential  diagnosis,  as  in  infantile  myxedema  the  delay  in 
growth  and  that  in  the  occurrence  of  the  bone  nuclei  is  very  evident.  On  the 
contrary,  there  occurs  in  true  infantilism  and  in  hypophysial  dwarfism  an  en- 
tirely similar,  although  in  most  cases  not  such  a  severe,  delay  in  ossification 
as  in  infantile  myxedema.  It  is  true  that  growth  in  infantilism  may  some- 
times be  hastened  through  thyroid  medication,  but  not  in  such  a  manner  as 
in  sporadic  cretinism.  Hypophysial  dwarfism  tends  to  behave  similarly  (see 
Chap.  VI).  In  both  conditions,  moreover,  the  assimilation  boundaries  for 
thyroidin  lie  essentially  lower  than  in  sporadic  cretinism. 

The  distinguishing  of  the  etiologically  dift'erent  forms  of  cretinism  in  vivo 
is  often  difficult,  and  in  many  cases  quite  impossible.  Light  cases,  or  those  in 
which  the  delay  in  development  sets  in  at  a  later  stage  are  to  be  counted  as 
infantile  myxedema.  In  the  severe  cases  that  occur  quite  early  the  assump- 
tion of  a  thyroaplasia  is  better  warranted,  but  is  not  to  be  relied  on  in  vivo, 
as  the  negative  finding  on  palpation  is  valueless. 

We  shall  consider  in  the  third  chapter  the  delimitation  from  endemic 
cretinism. 


TREATMENT  OF  ATHYROSIS  AND  HYPOTHYROSIS  I39 

Treatment  of  Athyrosis  and  Hypothyrosis 

Light  grades  of  thyroid  insufficiency  may  heal  spontaneously  or  under  the 
use  of  thyroid-gland  tablets  (probably  on  account  of  the  stimulating  action 
of  the  iodine  they  contain  on  the  thyroid  and  on  account  of  the  raising  of 
all  metabolic  process-es).  In  the  severe  cases,  and  especially  those  with  com- 
plete absence  of  the  thyroid,  an  ideal  therapy  would  be  the  implantation  of 
a  new  thyroid  gland. 

Already  A.  Schijf  tried  to  remedy  the  deficiency,  in  animals  in  whom  the 
thyroid  gland  had  been  extirpated,  by  the  implantation  of  a  new  thyroid. 
H.  Bircher  was  the  first,  in  1889,  to  succeed  in  the  implantation  of  a  thyroid 
in  a  case  of  very  severe  cachexia  strumipriva.^  He  implanted  with  good  re- 
sults a  human  thyroid  into  the  abdominal  cavity;  there  soon,  however,  occurred 
a  relapse.  A  new  implantation  brought  about  considerable  improvement, 
indeed  even  there  w^as  a  return  of  the  menses,' w^hich  had  ceased  for  a  year; 
but  this  result  too  was  not  permanent.  Later  Collins  and  Macpherson  re- 
ported results  in  myxedema  that  lasted  from  one  and  one-half  to  two  years. 
In  these  cases  there  were  many  renewed  transplantations.  Even  more 
favorable  results  are  reported  by  Gibson  and  others  in  sporadic  cretinism, 
fi'or.y/gy  proposed  that  thyroids  of  monkeys  or  sheep  be  transplanted  under  the 
skin  of  the  breast,  Rehn  under  the  skin  of  the  throat.  New  hopes  were  aroused 
by  the  attempt  of  Payr  to  transplant  thyroid  tissue  into  the  spleen,  at  first  in 
animals,  later  in  a  four-year-old  case  of  sporadic  cretinism.  In  the  case  last 
mentioned  the  thyroid  tissue  came  from  the  mothers.  There  occurred  an 
essential  improvement  which  aft"ected,  in  addition  to  the  myxedematous 
symptoms  referable  to  the  skin,  also  the  intelhgence  and  the  growth  of  bone 
(12  cm.  in  five  months).  But  also  in  this  case  the  result  was  not  permanent. 
Kocher  suggested  transplanting  thyroid  gland  into  the  bone  marrow.  Mos- 
zkowicz  implanted  thyroid-gland  tissue  into  the  tibia  of  a  six-year-old  myxe- 
dematous child.  Here  too  the  result  was  good,  but  only  transitory.  (Per- 
sonal communication.)  Also  the  results  attained  by  Bramann  seem  to  have 
been  only  transitory. 

New  hopes  have  been  awakened  through  the  important  investigations  of 
Carrel  on  the  suture  of  vessels.  Stich  and  Makkas  succeeded  in  doing  auto- 
plasty  on  dogs;  heteroplasty  did  not  however  succeed.  Enderlen  and  Borst 
come,  on  the  ground  of  their  interesting  experiments,  to  the  conclusion  that 
autotransplantation,  that  is,  the  transplantation  of  the  thyroid  gland  from 
one  part  of  the  body  to  another  of  the  same  individual  represents  per- 
manent results.  Homiotransplantation,  that  is  the  transplantation  of  the 
thyroid  gland  of  an  individual  to  another  of  the  same  species,  for  instance, 
from  dog  to  dog,  or  from  goat  to  goat,  remained  without  results  even  when 
the  animals  were  from  the  same  parents.  The  vessel  suture  indeed  healed, 
1  The  experiments  of  v.  Eiselsberg  are  of  extraordinary  interest  for  tetany  and  will  be  con- 
sidered under  that  caption. 


I40  THE    DISEASES    OF    THE    THYROID    GLAXD 

the  vessels  remained  patulous,  the  glands  however  became  absorbed.  Ex- 
periments on  cretins  likewise  led  to  negative  results.  The  thyroid  artery 
and  vein  from  the  upper  pole  of  the  thyroids  obtained  from  struma  operations 
on  man  were  united  to  the  axillary  vessels  of  the  cretins;  but  here  also  there 
came  about  a  gradual  absorption  of  the  glands.  Enderlen  and  Borst  con- 
cluded that  already  the  slight  biochemical  differences  that  exist  between 
the  tissues  of  different  individuals  of  the  same  species  are  sufficient  to  prevent 
a  permanent  functionating  of  the  engrafted  organ. 

Therefore  the  sovereign  method  of  treatment  to-day  is  still  the  administration 
of  tJiyroid-gland  substance. 

Murray  first  proposed  the  treatment  of  myxedema  with  carbolated  glyc- 
erin extracts  from  the  thyroids  of  animals  and  practised  this  with  good 
results.  Also  Kocher.  LeicJitenstern.  Eicald,  and  others  saw  good  results. 
Since  that  time,  however.  Fox,  Mackoizie,  and  others  found  that  they  could 
succeed  in  inducing  the  action  of  the  active  principle  also  by  administering  it 
by  mouth;  this  method  superseded  all  others  and  to-day  is  alone  practised. 
At  the  beginning  one  saw  individual  cases  of  severe  acute  intoxication.  In 
many  of  these  death  occurred  with  profuse  diarrhea  after  the  ingestion  of  a 
very  slight  amount  of  thyroid-gland  substance.  Here  the  effect  must  have 
been  due  to  putrefied  preparations,  as  the  symptoms  deviated  from  those  of 
thyroidin,  and  the  latter  appeared  only  after  the  ingestion  of  much  larger 
doses. 

Of  the  numerous  thyroid-gland  preparations  that  are  found  on  the  market 
to-day  the  tablets  of  Burroughs,  Wellcome  &"  Co.  [England]  and  those  of 
Parke,  Davis  &f  Co.  [America]  are  characterized  by  the  intensity  and  uni- 
formity of  their  action.  They  consist  of  dried  sheep  thyroid  and  come 
on  the  market  in  doses  of  0.1-0.3  gm. 

Of  other  preparations  I  mention  the  thyreoidinum  siccatum  (Merck), 
thyraden  (Kocher),  in  pills  or  tablets  representing  0.0007  gni.  iodine,  and  iodo- 
thyrin  or  thyroiodin  (5(zyer) .  i  gm.  contains  3  mg.  active  substance  or  0.3 
mg.  iodine,  representing  the  iodine  content  of  i  gm.  fresh  lamb's  thyroid. 

According  to  the  investigations  of  Fonio,  the  action  of  thyroid  prepara- 
tions on  the  metabolic  processes  (protein  decomposition,  diuresis,  body 
weight,  etc.)  parallels  their  iodine  content.  This  does  not  hold  good  for  all 
actions  of  the  thyroid-gland  substance.  For  instance  there  occurred  in  my 
own  experiments  with  iodothyrin  in  every  dose  (to  7  gm.  daily)  action  on  the 
metabolism  much  greater  than  that  on  the  cardiovascular  apparatus.  Then, 
too,  much  larger  doses  of  iodothyrin  than  of  tabloids  are  needed  to  induce 
symptoms  of  hyperthyroidism.  In  his  substitution  experiments  Magnus- 
Levy  ascribes  to  iodothyrin  the  same  activity  as  that  of  thyroidin.  It  is  quite 
undoubted  that  iodothyrin  exerted  a  powerful  influence  on  the  fundamental 
exchange  of  Magnus-Levy's  patients — yet  we  cannot  make  out  from  Magnus- 
Levy's  protocols  whether  on  long-continued  administration  also  the  influence 


TREATMENT  OF  ATHYROSIS  AND  HYPOTHYROSIS  14I 

on  bone  growth  was  the  same.  According  to  this  it  is  not  at  all  likely  that,  as 
Pick  and  Pineles  state,  in  young  thyroprivic  dogs  the  symptoms  of  deficiency 
are  not  fully  combated  by  iodothyrin,  but  that  they  are  combated  by  the 
English  tablets. 

Thyroantitoxin,  potassium  iodide,  and  hypophysis  substance  are,  as 
shown  by  the  experiments  of  Magnus-Levy,  entirely  actionless. 

As  far  as  the  dose  is  concerned,  it  is  well  in  every  case  to  begin  with  small 
doses  and  gradually  to  increase.  In  adults  we  give  one  to  two  English  tablets 
daily  and  can  gradually  increase  to  from  three  to  five.  If  we  have  attained 
a  favorable  result,  we  may  again  decrease  the  dose  to  two  or  one  tablet. 
Children  are  usually  first  given  one-half  tablet,  which  may  be  increased  to 
from  two  to  three  tablets.  In  my  cases  of  sporadic  cretinism  I  went  transi- 
torially  as  high  as  seven  tablets,  in  one  case  indeed  to  nine.  Kassowitz  recom- 
mends thyreoid  elixir  {Alle?i  H anbury,  ~London),  of  which  one  coffee-spoonful 
represents  about  one-sixth  of  a  sheep's  thyroid  gland.  Children  under  a  half 
year  should  be  given  one-half  coffee-spoonfuFdaily,  later  increased  to  one 
coffee-spoonful.  Only  in  children  over  twelve  years  of  age  did  Kassowitz 
order  up  to  two  coffee-spoonfuls  per  day. 

The  result  of  thyroid-gland  medication  in  myxedema  adultorum  is  in  the 
most  cases  an  immediate  one.  The  myxedematous  swellings  may  undergo 
an  appreciable  reduction  even  in  a  few  days.  Together  with  this  there  goes 
for  the  most  part,  a  loss  of  the  body  protein,  that  for  the  most  part  depends 
on  the  rapid  melting  down  of  the  myxedematous  tissue.  In  the  cases  in 
which  very  marked  swellings  have  occurred,  the  skin  is  lax  and  wrinkled. 
It  acts  very  rapidly  on  the  secretion  of  sweat,  in  that  the  previously  dry 
skin  becomes  moist;  then  too,  the  marked  scaling  ceases.  The  action  on 
the  trophic  disturbances  naturally  takes  a  long  time,  but  are  no  less  striking. 
The  bald  spots  on  the  head  cover  again  with  new  hair;  the  hair  on  the  axillse 
and  on  the  genitalia  become  thicker,  the  hairs  again  feel  soft  and  pliable. 
The  pulse  becomes  more  rapid,  the  protein  exchange  and  the  fundamental 
exchange  rise  to  normal,  the  appetite  increases,  the  beginning  loss  of  weight 
supersedes  the  gradual  increase  in  weight.  The  diuresis  becomes  more  abun- 
dant, the  lowered  temperature  rises  at  first  somewhat  above  the  normal,  and 
then  remains  normal.  The  action  on  the  blood  is  usually  slower;  usually 
a  medication  of  several  weeks'  or  several  months'  duration  is  required 
before  the  red  cells  and  the  amount  of  hemoglobin  come  back  to  normal  and 
before  the  differential  counts  of  the  white  cells  show  normal  values.  The 
mental  condition  improves  much  more  rapidly.  The  apathy  may  appreci- 
ably improve  after  only  a  few  days,  the  patients  become  more  active,  they 
take  a  more  active  interest  in  their  environment,  and  the  memory  improves. 
Also  the  mental  disturbances  accompanying  the  myxedematous  condition 
show  a  pronounced  improvement  and  under  the  thyroid  medication  may  even 
become  entirely  normal.     In  the  case  of  Pilcz  already  mentioned  the  illusive 


142  THE    DISEASES    OF    THE    THYROID    GLAXD 

ideas  disappeared  entirely;  with  the  withdrawal  of  the  medication  the  myxe- 
dema and  also  the  mental  disturbance  recurred.  A  renewal  of  the  therapy 
again  brought  about  cure,  that  remained  definite  in  spite  of  discontinuation  of 
the  treatment.  This  patient  had  a  goiter.  Pilcz  supposes  that  in  this  case 
the  thyroid  gland  regained  its  activities  through  the  stimulating  influence  of 
thyroid  medication.  Also  the  hardness-of-hearing  sometimes  accompanying 
myxedema  often  shows  a  decided  improvement.  The  English  Myxedema 
Commission  found  that  among  one  hundred  and  nine  cases  of  myxedema, 
nearly  the  half  showed  disturbances  of  hearing;  this  disappeared  under 
thyroid  treatment.  Also  speech  becomes  livelier,  even  at  the  beginning 
of  treatment,  as  Magnus-Levy  states.  In  many  of  the  cases  stuttering 
appears  at  the  beginning  of  the  medication.  Gutzmann  explains  this  in  the 
fact  that  the  desire  for  speaking  becomes  rapidly  increased,  while  there  is  a 
certain  awkwardness  of  speech  due  to  inhibition  of  the  peripheral  speech 
mechanism  (swelling  of  the  mucous  membrane  of  the  mouth,  the  nose,  the 
throat,  and  slight  mobility  of  the  velum  palati).  Then,  too,  the  disturbances 
in  the  sexual  sphere  improve,  often  astonishingly.  The  dysmenorrhea  dis- 
appears, the  long-absent  menstruation  may  recur,  in  men  potency  may 
again  return.     Existing  albuminurias  tend  to  disappear. 

The  results  of  thyroid  medication  in  typical  cases  is  to  be  regarded  as 
almost  certain.  Already  Heinzheimer  has  collected  one  hundred  and  fifty 
cases  from  the  literature  in  which  a  complete  favorable  result  was  brought 
about  by  the  treatment.  Cure  can  occur  even  when  myxedema  has  existed 
for  a  long  time.  In  a  case  of  Dunlop  the  myxedema  had  existed  for  twelve 
years. 

In  the  cases  of  formes  frustes  of  myxedema  the  results  are  just  as  satis- 
factory. Especially  in  the  cases  of  thyrogenic  obesity,  thyroid  medication, 
as  already  mentioned,  brings  about,  with  diet  freely  chosen  and  with  improve- 
ment of  the  general  conditions,  a  rapid  reduction  in  weight,  while  marked  re- 
duction of  the  caloric  supply  only  produces  conditions  of  weakness. 

Sometimes,  indeed,  the  results  of  thyroid  medication  in  myxedema  are  not 
so  revolutionary.  In  the  first  place  it  may  happen  that  on  account  of  the  long 
duration  of  the  disease  more  deeply  seated  disturbances  have  developed, 
for  example,  high-grade  anemia,  which  then  furnishes  a  slight  resistance  to 
the  administration  of  thyroid  gland.  In  other  cases  symptoms  of  thyroidism 
rapidly  appear,  which  call  for  the  limitation  or  eventually  the  discontinuation 
of  the  agent.  In  such  cases  it  may  happen  that  the  symptoms  of  myxedema 
are  only  a  little  influenced  while  tachycardia,  insomnia,  excitation,  etc.,  make 
their  appearance  rapidly.  Such  a  case  was  first  described  by  Beclcre.  Here 
the  myxedema  gradually  disappeared.  There  occurred,  however,  rapid  loss 
of  weight,  tachycardia,  insomnia,  excitations,  polyuria,  albuminuria,  partial 
paraplegia,  sensation  of  heat,  sweats,  tachypnea,  transitory  tremor,  and  a 
slight  grade  of  exophthalmus. 


TREATMENT  OF  ATHYROSIS  AND  HYPOTHYROSIS  I43 

Mahille  believes  that  the  simultaneous  administration  of  small  doses  of 
arsenic  prevents  the  occurrence  of  symptoms  of  hyperthyroidism.  Eicald 
agrees  with  him.  Magnus-Levy  missed  this  action  of  arsenic.  Hertoghe 
warns  against  the  administration  of  alcohol  or  morphine  during  the  th3Toid 
medication.  He  recommends  administration  of  sodium  bicarbonate,  or, 
when  diarrhea  occurs,  of  bismuth. 

In  general  we  may  well  assume  that  typical  cases  of  myxedema  show  a 
high  tolerance  for  thyroidin.  When  manifestations  of  thyroidism  occur,  the 
cause  of  these  may  lie  in  a  simultaneous  degeneration  of  the  heart  muscle, 
that  reacts  more  quickly  to  thyroid  medication,  or  we  are  probably  not  deal- 
ing with  typical  myxedema,  but  with  a  combination  of  myxedema  symptoms 
with  symptoms  of  deficiency  on  the  part  of  the  other  ductless  glands  (see 
multiple  sclerosis  of  the  ductless  glands). 

The  action  of  thyroid  medication  in  sporadic  cretinism  deviates  in  many 
points  from  that  just  described.  On  the  one  hand,  there  here  occurs  a  num- 
ber of  other  disturbances  which  relate  to  the  existing  disturbances  in  develop- 
ment (growth  in  size,  dentition,  sexual  sphere,  etc.);  on  the  other  hand,  it 
is  intelligible  that  with  the  long  existence  of  the  inhibition  of  development 
degenerative  conditions  have  become  established  that  are  no  longer  reparable. 
Very  significant  results  are  hence  to  be  expected  only  in  light  forms  or  when 
the  treatment  has  been  started  early.  Very  significant  seems  to  be  the 
influence  on  growth.  Already  in  i8g6,  Buschan  collected  from  the  literature 
thirty-two  cases  which  showed  rapid  growth  under  thyroid  medication. 
Latterly,  statements  as  to  this  subject  have  considerably  increased. 

X-ray  examination  shows  that  with  the  increased  growth  in  height  there 
occurs  rapid  appearance  and  growth  of  the  bone  nuclei,  or  rapid  ossification 
of  the  epiphysial  junctures. 

Hertoghe  states  that  in  myxedematous  children  under  certain  circum- 
stances, administration  of  thyroid  may  lead  to  such  a  rapidly  increased 
growth  in  height  that  scoliosis  or  k>"phoscohosis  develop.  In  the  fully 
developed  form  of  sporadic  cretinism  in  which  the  epiphysial  junctures  are 
often  fully  open  in  the  third  and  fourth  decade,  there  may  still  occur  under 
thyroid  medication,  appreciable  growth  in  height  and  finally  closure  of  the 
epiphysial  junctures  and  the  fontanelles. 

As  is  the  case  with  ossification,  the  previously  retarded  dentition  also 
shows  a  sudden  acceleration.  I  cite  from  the  reports  of  Kassowitz  the 
following  example:  A  twenty- two-month-old  child  had  not  a  single  tooth; 
after  a  six  months'  treatment  sixteen  teeth  had  erupted.  A  similar  accelerat- 
ing influence  is  exercised  on  the  formation  of  the  permanent  teeth.  A  ten- 
year-old  girl  had  only  remnants  of  the  milk-teeth;  after  one  year's  treatment 
she  possessed  six,  after  two  years'  treatment  eighteen  permanent  teeth. 
Very  pretty  examples  of  the  stimulation  of  growth  through  thyroid  medica- 
tion are  found  also  in  Oppenheim's  text-book  of  neurology  and  in  Siegert. 


144  THE    DISEASES    OF    THE    THYROID    GLAND 

Under  the  influence  of  the  medication  the  umbiHcal  hernias  disappear, 
not  rarely  in  a  few  weeks,  sometimes  after  a  month.  These  are  almost 
constant  in  infantile  myxedema,  and  often  appreciably  large. 

Finally,  just  as  significant  is  the  influence  on  the  genitalia  and  the  second- 
ary sexual  characters.  Magnus-Levy  reports  the  case  of  a  forty-five-year-old 
cretin,  in  whom  at  the  beginning  of  medication  the  pubic  hair  began  to 
develop  and  the  penis  began  to  increase  in  size.  In  a  case  of  cachexia 
strumipriva.  in  whom  the  struma  had  been  totally  extirpated  at  the  age  of 
fourteen,  thyroid  medication  was  begun  in  the  twenty-eighth  year.  Al- 
ready after  two  years  there  was  noticed  a  certain  sexual  development,  after 
seven  years  all  sexual  characters  were  present  and  sexual  maturity  was  at- 
tained. In  the  fully  developed  form  of  sporadic  cretinism  it  is  not.  of  course, 
to  be  expected  that  a  late-introduced  treatment  is  able  to  bring  about  pro- 
creative  capacity. 

Also  the  mental  development  takes  part  in  this  general  impetus. 

In  the  severe  cases  of  infantile  myxedema  permanent  administration  of 
thyroid  substance  is  necessary;  when  the  therapy  is  discontinued  relapses 
occur,  even  when  the  administration  of  the  larger  doses  have  transitorially 
brought  about  symptoms  of  h}perthyroidism  {Kndpjehnacher).  In  slight 
cases  the  result  is  mostly  a  permanent  one;  in  such  cases  we  assume  that 
under  the  stimulating  influence  of  the  therapy  the  thyroid  gland  has  held 
fast  to  its  development,  or  the  less  altered  parts  have  recovered. 

Thyroid  therapy  has  been  tried  in  a  great  number  of  disease  conditions  that 
have  nothing  directly  to  do  with  myxedema  and  is  often  very  much  valued. 
I  shall  speak  of  its  value  in  obesity  in  the  consideration  of  the  various  forms 
of  obesity  at  the  end  of  this  book.  Its  influence  in  diseases  of  the  h}'poph- 
ysis,  the  sexual  glands,  infantilism,  and  multiple  sclerosis  of  the  ductless 
glands,  I  shall  refer  to  in  the  appropriate  chapters.  Very  much  under  dis- 
cussion is  the  use  of  thyroidin  in  the  treatment  of  scleroderma.  Since 
Singer  first  reported  as  to  the  favorable  results  a  series  of  good  results  have 
been  published.  In  other  cases  there  were  soon  manifested  symptoms  of 
thyroidism  with  only  slight  improvement  of  the  sclerodermic  symptoms,  in 
still  other  cases,  finally,  the  treatment  failed  entirely.  The  literature  as  to 
this  subject  is  found  in  detail  in  Cassirers  communication,  v.  Xotthaft  is 
of  the  opinion  that  favorable  results,  where  they  have  been  obtained, 
depend  only  on  the  stimulation  of  the  general  metabolism  (consult  also  the 
statements  as  to  the  ductless  gland  theory  of  scleroderma  in  the  first  chapter). 
As  to  therapeutic  results  in  endemic  cretinism  see  the  next  chapter. 

Addendum 

With  regard  to  inflammations  of  the  thyroid,  cases  of  acute  idiopathic 
thyroiditis  have  been  reported  by  Dutrow  and  others.  In  Dutroiv's  case, 
which  was  accompanied  with  a  leucocytosis  of  12.000,  prompt  relief  was  ob- 


ADDENDUM  '  145 

tained  on  incision.  In  the  majority  of  cases,  such  energetic  treatment  will 
not  be  necessary.  The  application  of  cold  to  the  neck  in  this  case  is  a  means 
of  physical  treatment  that  must  not  be  forgotten  or  dispensed  with. 

The  question  of  dysfunction  in  the  cases  of  Basedow's  disease  has  by  no 
means  been  disposed  of,  and  in  America  has  attracted  no  less  an  authority 
than  Halsted,  who  has  been  much  impressed  with  recent  experiments  of, 
among  others,  Klose,  Lampe,  and  Liesegang.  Lampe  has  been  active  in 
applying  to  the  sera  of  Basedow's  patients  the  Abderhalden  reaction,  with 
various  organs  as  the  objects  to  be  acted  on,  with  the  result  that  he  finds 
present  in  the  sera  ferments  against  ovaries,  thyroid,  thymus,  and  no  other 
organs.  Deutsch  has  also  experimented  along  these  lines  and  has  found  that 
thymus  gland  tissue  is  split  up  also  by  normal  serum.  The  significance  of 
these  experiments  would  seem  to  point  to  some  defect  of  thyroid  secretions; 
whether  or  not  the  positive  results  of  the  experiments  mentioned  above  would 
tend  to  rule  out  simply  a  mere  excess  of  thyroid  secretion  is  not  known  to  the 
editor. 

The  fact  that  the  sera  act  on  ovaries  in  the  Abderhalden  test  would  point 
to  some  defect  in  ovarian  action.  It  is  well  known  that  Basedow's  disease  is 
often  associated  with,  in  addition  to  the  menstrual  disturbances  that  seem  to 
be  a  part  of  the  disease  itself,  pelvic  disturbances,  and  that  the  disease  is  often 
considerably  ameliorated,  if  not  cured,  with  the  remedying  of  these  pelvic 
conditions.  This  fact  has  been  repeatedly  pointed  out,  and  is  mentioned 
among  others  by  Porter.  According  to  Lampe,  dysfunction  of  the  branchio- 
genic  organs  leads  to  dysfunction  of  the  sexual  glands.  In  some  women, 
there  is  no  doubt  that  the  pelvic  or  the  sexual  trouble  has  led  to  marital  un- 
happiness,  this  even  when  there  is  no  gross  gynecological  lesion.  According 
to  Thomas,  who  in  speaking  of  the  subjects  of  exophthalmic  goiter  states  that 
"nearly  every  married  woman  with  whom  I  have  discussed  the  matter  has 
admitted  some  sort  of  incompatibility  with  her  husband,  and  since  it  almost 
always  appears  during  the  active  sexual  life,  I  strongly  suspect  a  distinct 
relationship." 

The  transition  into  the  sexual  sphere  leads  us  once  more  into  the  confines 
of  the  Freudian  hypothesis.  Scarcely  any  of  the  most  ardent  of  the  advo- 
cates of  Freud  would  venture  the  assertion  that  Basedow's  disease  is  the  re- 
sult of  a  suppressed  sexual  experience  of  childhood,  yet  such  a  Freudian  dis- 
ciple might  find  evidence  for  it  in  a  case  of  Basedow's  in  a  child  fifteen  years 
old,  that  I  saw  at  the  St.  Agnes  Hospital,  Philadelphia.  This  child  had  been 
the  victim  of  an  attempt  at  rape,  immediately  after  which  it  developed  the 
classical  symptoms  of  Basedow's  disease  (I  am  not  certain  as  to  the  pres- 
ence of  an  enlarged  thyroid)  and  almost  utter  inabihty  to  speak,  which 
symptoms  had  persisted  for  some  months.  I  am  not  certain  as  to  the  ulti- 
mate fate  of  the  child,  as  she  had  been  referred  to  the  hospital  from  a  country 
district,  and  paid  only  one  visit  to  the  hospital. 


146  THE    DISEASES    OF    THE    THYROID    GLAXD 

It  is  e\adent  that  in  the  above  case  the  sexual  element  if  present  at  all  was 
subordinate  to  that  of  the  factor  of  fright,  which  was  present  also  in  the 
present  case,  seen  by  me  at  the  St.  Agnes  Hospital.  It  was  that  of  a  highly 
religious,  intelligent  married  woman.  M.  H.,  aged  twenty-nine  years,  who 
during  the  strain  of  nursing  a  sick  father,  sustained  a  fright,  during  which 
she  found  that  a  burglar  had  entered  her  store.  A  few  weeks  later  her 
father  died.  Since  the  time  of  his  death  she  suffers  from  obsession  of 
a  religious  and  ''immoral"  nature,  in  the  course  of  which  she  dares  God  to 
do  his  worst  by  her,  and  wishes  harm  to  people.  Sometimes  the  obses- 
sions are  of  a  sexual  nature,  and  objects  in  her  environment  suggest  to  her 
thoughts  that  she  is  ashamed  of.  The  patient  dreams  very  much,  but 
none  of  the  dreams  have  a  sexual  content,  at  least  so  far  as  she  states. 
Her  mental  and  physical  conditions  have  improved  somewhat  recently,  in 
consequence  of  a  stay  at  a  sanitarium.  She  has  been  happily  married  for 
five  years,  shows  a  moderate  amount  of  libido  (it  increased  very  little  during 
the  earlier  stages  of  her  illness),  but  has  had  no  children,  not  because  she  uses 
means  to  prevent  conception,  but  because  according  to  a  doctor  her  "womb 
is  turned.''  There  is  some  evidence  of  hyper thyrosis,  tine  tremor,  pulse  112, 
rather  large  thyroid,  suggestion  of  exophthalmos,  leucopenia  of  2000  and 
various  accessory  signs  (tendency  to  looseness  of  bowels  rather  than  con- 
stipation, hair  has  become  finer  and  more  luxuriant). 

The  factor  of  fright  in  the  etiology  of  Basedow's  disease  has  been  empha- 
sized by  Crile,  whose  name  is  important  in  the  ductless  glandular  diseases  in 
general,  not  only  because  of  the  fact  that  he  has  developed  an  ingenious  theory 
for  the  explanation  of  certain  of  these  diseases  (especially  Basedow's  disease), 
but  also  because  of  his  theory  and  practice  of  treatment  in  operating  on  Base- 
dow's disease  and  in  general  (principle  of  anoci-associationj.  Crile  agrees 
with  the  author  that  Basedow's  disease  is  conditioned  by  a  state  affecting  the 
central  nervous  system ;  in  the  course  of  this  the  nerve  cells  of  the  cerebral 
cortex  become  chromatolytic,  at  the  same  time  that  the  cells  of  the  liver  and 
the  suprarenals  become  less  granular.  These  organs  together  with  the  thy- 
roid gland,  and  the  muscular  elements  constitute  the  kinetic  system,  the  pur- 
pose of  which  in  the  organism  is  the  conversion  of  potential  energy  into 
kinetic  energy.  The  above  changes,  if  I  understand  Crile  rightly,  are  more  or 
less  theoretical  for  Basedow's  disease,  but  have  been  obtained  by  him  in  a 
number  of  conditions  such  as  the  various  forms  of  traumatic,  emotional,  and 
toxic,  foreign  proteid,  and  anaphylactic  shock,  as  well  as  in  various  forms  of 
drug  poisoning  and  anemia.  As  has  been  stated,  Crile  has  formulated  on  the 
basis  of  theory  his  principle  of  anoci-association  upon  which  is  founded  a 
method  of  operating  in  which  the  deleterious  effects  of  shock  are  minimized 
by  a  combination  of  local  and  general  anesthesia.  The  method  has  been 
appHed  especially  to  operations  on  the  thyroid  gland.  Whether  or  not  the 
good  results  attest  to  the  truth  of  the  theorv,  or  whether  the  combination  of 


ADDENDUM  I 47 

the  two  forms  of  anesthesia  summate  in  some  other  way  is  of  theoretical  im- 
portance; practically,  the  good  results  speak  for  themselves,  and  are  attested 
to  by  Frazier  and  Muller.  The  method  is  attended  with  a  number  of  refine- 
ments of  technique  for  the  consideration  of  which  the  reader  is  referred  to 
Crile^s  work.  One  of  the  important  factors  is  a  sort  of  psychic  treatment, 
consisting  in  the  fact  that  the  patient  is  gradually  habituated  on  successive 
days  to  the  method  of  general  anesthesia,  while  under  the  impression  that 
he  is  receiving  treatments.  As  has  already  been  stated  at  another  place, 
Crile's  theory  is  based  on  observations  on  40,000  nerve  cells,  and  forms  an 
interesting  explanation  for  the  role  of  the  central  nervous  system  in  the 
etiology  of  Basedow's  disease. 

The  effect  of  thyroid  secretion  on  the  central  nervous  system,  the  close 
connection  of  the  central  nervous  system  with  the  thyroid  is  instanced  in  the 
association  of  epilepsy  with  thyroid  disease,  especially  exophthalmic  goiter. 
This  association  which  is  acknowledged  cursorily  by  Kocher  and  Gushing  was 
pointed  out  by  the  translator  some  time  ago.  It  is  interesting  that  a  short 
time  after  the  translator  presented  his  cases,  through  courtesy  of  Potts  he 
presented  the  history  of  an  adult  female  who  developed  epileptiform  convul- 
sion for  the  first  time  after  the  use  of  double  the  prescribed  doses  of  thyroid 
extract.  It  is  probable  that  in  this  case,  and  in  some  of  the  cases  previously 
reported  by  the  translator,  the  thyroid-gland  substance  acted  as  a  toxic 
agent  on  a  central  nervous  system  already  predisposed  to  the  occurrence  of 
epilepsy.  It  is  interesting,  however,  that  the  thyroid  extract  is  one  of  the 
metabolic  products  that  acts  in  this  way. 

With  regard  to  the  laboratory  symptomatology  of  Basedow's  disease, 
Kocher  has  corroborated  his  conclusions  as  to  the  blood  picture  in  Basedow's 
disease  by  over  670  cases  that  have  been  operated  on.  He  regards  the  blood 
examination  as  of  the  greatest  diagnostic  importance  in  light  and  obscure 
cases  of  Basedow's  and  myxedema.  In  155  cases  of  myxedema  there  were 
only  twenty-six  that  did  not  show  a  leucopenia.  The  degree  of  absolute 
leucopenia  is  more  considerable  than  in  Basedow's  disease,  lying  between  3000 
and  6000.  Lymphocytosis  lies  between  30-40  per  cent,  less  than  in  Base- 
dow's disease.  The  mast-cells  are  0.2-0.4  per  cent.  In  myxedema  the 
coagulation  time  is  decreased,  to  as  low  as  six  minutes.  This  hastening  of 
coagulation  is  very  constant.  The  blood  picture  approaches  the  normal 
with  favorable  therapeutic  procedures. 

Cases  of  diffuse  colloid  goiter  approach  the  type  of  blood  picture  of  myxe- 
dema. Nodular  goiters  show,  as  a  rule,  a  normal  blood  picture,  or,  occasion- 
ally that  of  hyperthyrosis. 

This  blood  picture  has  been  much  discussed,  and  is  worthy  of  even  more 
close  study  than  it  has  received,  especially  in  view  of  the  more  recent  studies 
of  the  pathology  of  the  thyroid  gland  in  goiter  by  Wilson  and  by  Plummer, 
stated  below. 


148  THE    DISEASES    OF    THE    THYROID    GLAND 

Fonio's  experiments  have  shown  that  when  thyroid  or  colloid  goiter  or 
Basedow's  struma  preparations  are  administered  to  myxedemics  there 
occurred  an  increased  elimination  of  nitrogen,  increased  diuresis,  and  de- 
crease of  the  body  weight,  and  that  the  nitrogen  elimination  varied  directly 
as  the  iodine  content  of  the  preparation  administered.  In  the  two  cases 
he  worked  on,  he  was  unable  to  substantiate  a  hyperleucocytosis  or  an 
eosinophilia. 

In  passing,  the  editor  would  state  that  in  America  the  condition  myxe- 
dema seems  to  be  relatively  rare. 

So  far  as  the  pathology  of  the  thyroid  gland  is  concerned,  MacCarty, 
from  a  study  of  over  2500  thyroid  glands  removed  at  operation,  divided  these 
into  the  symmetrical  and  the  asymmetrical  or  nodular.  The  symmetrical 
glands  contain  various  combinations  of  an  adult  and  a  fetal  type  of  tissue 
element  or  of  hypertrophied  acini  containing  colloid,  or  of  acini  that  contain 
little  or  no  colloid  material,  but  that  possess  lumina  almost  completely  filled 
with  large  hypertrophic  or  hyperplastic  cells.  The  simple  nodular  or  simple 
symmetric  thyroids  contain  nodules  with  a  fetal  type  of  cell,  while  the  re- 
mainder of  the  parenchyma  of  the  thyroid  gland  possesses  various  combina- 
tions of  the  tissue  elements  described  under  the  symmetric  thyroids.  The 
complex  nonsymmetric  thyroids  may  show,  in  addition,  various  combina- 
tions of  the  tissue-element  types  in  the  nodules. 

Still  more  recent  studies  on  the  pathology  of  the  thyroid  gland  have  been 
made  by  Wilson  and  by  Plummer,  who  base  their  conclusions  on  the  enormous 
material  of  the  Mayo  Clinic.  These  authors  divide  goiters  with  symptoms 
of  intoxication  into,  clinically,  the  exophthalmic  and  nonexophthalmic 
forms.  In  the  first  form  only  is  there  a  true  hypertrophy  and  hyperplasia 
of  the  gland  tissue.  The  pathology  of  toxic  nonexophthalmic  goiter  is  one 
of  increased  parenchyma  through  regenerative  changes  in  atrophic  paren- 
chyma, or  the  formation  of  new  parenchyma  of  the  fetal  type  with  an  increase 
in  each  instance  of  secretory  activity  and  of  absorption.  The  process  is  a 
chronic  one,  but  one  suflficiently  active  to  cause  the  patient  to  consult  a 
surgeon  earlier  than  do  the  true  exophthalmic  goiter  patients,  in  whom  the 
disease  is  acute. 

Gilbride  has  examined  the  thyroids  in  six  cases  of  exophthalmic  goiter 
bacteriologically,  and  isolated  a  bacterium  in  one  case  only — micrococcus 
tetragenes. 

With  regard  to  the  treatment  of  Basedow's  disease,  internists  and 
surgeons  occupy  hostile  camps.  More  and  more  has  the  opinion  gained 
ground  that  the  condition  is  an  affection  demanding  surgical  attention. 
Nevertheless  border-line  cases  should  first  be  given  the  benefit  of  properly 
directed  medicinal  dietary  and  physiotherapeutic  measures. 

S.  Solis-Colicn  has  a  strong  conviction  that  surgical  measures  are  indicated 
only  in  a  small  minority  of  the  cases  of  exophthalmic  goiter  that  come  under 


ADDENDUM  I49 

the  eye  of  the  alert  physician.     He  recognizes  the  following  indications  for 
treatment. 

1.  When  the  disease  has  persisted  and,  despite  proper  medical  and  hy- 
gienic care,  is  advancing. 

2.  When  the  disease  is  progressive  or  far  advanced. 

3.  When  the  patient's  means  or  social  status  is  such  that  rest  is  im- 
practicable, and  the  disease,  although  slight,  has  persisted  under  treat- 
ment for  a  year  or  more  without  signs  of  yielding. 

This  author  estimates  the  number  of  cases  in  which  surgical  intervention 
is  necessary  at  about  5  per  cent,  of  the  total  number.  He  recommends  in- 
dividualization in  treatment,  the  keynote  of  which  is  rest.  Correction  of 
the  eye  conditions,  fresh  air,  proper  diet,  the  drinking  of  hot  water  for  its 
diuretic  and  eliminative  action,  intestinal  antiseptics,  neutral  quinine  hydro- 
bromide  (5  gr.  or  more  thrice  daily),  ergot,  picrotoxin,  calcium  chloride,  digi- 
talis, strophanthus,  and  even  cactus  all  have  their  place  in  the  medicinal 
therapy.  In  addition  hydrotherapeutic  measures,  electricity  (ionic  appli- 
cation of  iodine  to  the  gland  or  to  the  cervical  sympathetic,  or  the  high- 
frequency  discharge  to  the  neck  or  to  the  vertebra  prominens)  and  the  ice- 
bag  or  ice-coil  to  the  heart  or  gland  or  spine.  Among  organic  extracts  the 
author  recommends  especially  thymus  extract  (0.5-3  gni-  per  diem)  or  a 
combination  of  thymus  gland  with  adrenalin. 

Falta  has  in  the  text  cited  the  fact  that  in  many  cases  of  Basedow's  the 
thymus  gland  is  enlarged.  The  use  of  thymus  extract  in  Basedow's  disease 
had  better  be  dispensed  with.  The  editor  would  advise  against  the  employ- 
ment of  adrenalin  on  account  of  the  tendency  to  glycosuria  in  Basedow's 
disease. 

Musser  summarizes  the  results  of  consideration  of  medical  and  surgical 
treatment  in  the  dealing  with  goiter,  especially  exophthalmic  goiter,  as 
follows : 

1.  "Endemic  goiter  should  not  be  treated  surgically  until  proper  general 
treatment  has  been  employed  for  a  long  time. 

2.  Surgical  intervention  should  not  be  advised  in  cases  of  goiter  associated 
with  functional  or  organic  disturbances  of  other  secretory  organs 
until  the  associated  disorders  are  removed  or  relieved. 

3.  If  relapses  occur  in  spite  of  general  treatment,  or  in  spite  of  treatment 
directed  against  the  disorders  of  other  organs,  a  goiter  should  then  be 
treated  surgically. 

4.  Medical  treatment  should  be  continued  from  six  to  twenty-four  months. 
Favorable  results  should  not  be  promised  unless  the  patient  is  under 
the  absolute  control  of  a  physician,  so  that  treatment  by  rest,  diet, 
bathing,  physical  therapy  and  so  forth  may  be  carried  out  with  pre- 
cision and  continuity. 


150  THE    DISEASES    OF    THE    THYROID    GLAND 

5.  Surgical  intervention  requires  the  same  rigid  and  prolonged  after- 
treatment  to  give  permanent  results." 

Musser  believes  that  the  surgeon  does  too  much,  the  internist  too  little, 
in  the  treatment  of  goiter. 

Ahrams  recommends  for  exophthalmic  goiter  stimulation  of  the  vagus 
nerve  by  direct  percussion  or  concussion  over  the  seventh  cervical  spine. 
In  addition,  he  recommends  pilocarpine,  hypodermically  or  in  doses  of  Jf  0 
gr.  three  times  daily  by  mouth.  With  regard  to  this  treatment  it  may 
be  said  that  Abrams  uses  it  to  give  tone  to  the  vagus  nerve.  If  it  is  granted 
that  this  method  of  procedure  really  does  stimulate  the  vagus  nerve,  the 
treatment  is  certainly  not  indicated  in  the  so-called  vagotonic  forms  of  the 
disease. 

Stoney  reports  forty-one  cases  of  exophthalmic  goiter  (various  types) 
treated  by  X-rays.  (The  anode  is  6  in.  from  the  skin,  which  is  protected  with 
four  layers  of  blankets.  One-half  to  i  milliampere  of  current  is  run  through 
the  secondary.)  Of  the  forty-one  cases  fourteen  were  completely  cured,  some 
of  these  remaining  well  for  over  two  years  after  the  treatments,  twenty-two 
more  have  improved  very  much,  four  were  somewhat  better,  only  one  did  not 
do  well.  Snow  in  a  discussion  of  Stoney' s  report  stated  that  he  had  seen  good 
results  from  the  application  of  the  static  wave  current,  and  from  the  use  of 
Abram's  percussion  method. 

Lewi  reports  a  series  of  thirty-four  cases  of  exophthalmic  goiter  and 
perverted  thyroid  secretion  [?]  that  he  treated  with  high-frequency  currents, 
with  results  that  he  considers  exceptionally  good. 

The  editor  believes  that  no  harm  is  done  by  expectant  treatment  with  high- 
frequency  currents,  combined  with  rest  and  other  rational  methods  of  physio- 
therapeutics; and  that  such  currents  might  be  used  as  an  alternative  for  the 
X-rays,  or  as  a  substitute  for  them  before  they  are  used.  Temporizing  with 
such  methods  should  not,  however,  supersede  surgical  procedures  in  appro- 
priate cases.  The  use  of  radium  is  mentioned  by  Marine  in  a  review,  and 
Turner  reports  that  results  from  local  irradiation  with  radium  were  as  favor- 
able as  those  of  the  X-ray. 

After  hearing  what  these  internists  and  physiotherapeutists  have  to  say 
let  us  turn  our  attention  to  the  surgical  side  of  the  question.  According 
to  Mayo,  the  early  operation  of  ligation  cures  many  cases.  Early  as  well  as 
advanced  cases  can  be  cured  by  partial  thyroidectomy.  The  mortality  in 
these  cases  will  vary  from  i  to  4  per  cent.  Combined  operations  are  often 
indicated  in  bad  cases:  first  ligating  one  or  both  superior  vessel  areas,  and, 
later,  doing  a  partial  thyroidectomy. 

Local  anesthesia  is  indicated  in  most  ligations.  Local  or  combined  or 
straight  ether  anesthesia  are  the  methods  used  for  thyroidectomies,  according 
to  the  preference  or  experience  of  the  individual  operator. 

In  900  operations  performed  on  the  thyroid  in  St.   Mary's  Hospital, 


ADDENDUM 


i5i 


Rochester,  Minn.,  during  the  first  ten  months  of  191 1.  the  mortahty  was  i 
per  cent. 

Halsted  in  his  recent  article  on  thymectomy  as  a  surgical  procedure  in 
the  treatment  of  Basedow's  disease  publishes  the  following  instructive  table, 
which  he  in  turn  has  copied  from  Klose  (Die  Basedowsche  Krankheit,  Ergebn. 
d.  inn.  Med.  u.  Kinderh.,  Band  X,  1913). 


Results  of  Operations  for  Basedow's  Disease 


Year 


No.  of 
cases 


Cures, 
per 
cent. 


Considerable 

improvement, 

per  cent. 


I 

90 

.0 

! 

66 

6 

66 

5 

40 

9  , 

76 

0  i 

60 

0 

67 

5 

50 

2 

87 

5 

72 

0 

93 

St 

7 
7 

78 

2 

50 

2 

16 

9  : 

93 

2 

14 

5 

38 

I 

84 

6 

72 

5 

61 

4  ' 

70- 

0 

75 

5 

60. 

0 

Slight 
improve- 
ment, 
per  cent. 


Xo 
im- 
prove- 
ment, 
per 
cent. 


Deaths, 
I     per 
cent. 


1900 
1900 
1902 
1902 
1903 
1904 
1905 
1905 
1906 
1907 
1907 
1907 
1907 


1909 
1909 
1911 
1911 
1911 
1911 
1912 
1912 


Schultz I  20 

Wolf.... 9 

Helferich '  6 

Reinbach  (V.  Mikulicz) 18 

Witmer  (Kronlein) 23 

Th.  Kocher 59 

Curtis II 

Mayo 40 

Lessing  (Konig) ■  8 

Hartley 21 

K.  Schultze  (Riedel) 50 

A.  Kocher 167 

Itzina 7 

Mayo  (only  new  cases) ,  136 

Landstrom I  54 

Moses  (Garre) i  28 


32 
153 


26 


Klemm 

Th.  Kocher 

MacCosh 

Hanel 

Sudeck 

Baruch 1     40 

V.  Eiselsburg 44 

Enderlen 40 

Klose 61 

Weispfenning 30 


16.7 
22.5 
36.2 
14.0 
10. o 
17-5 


19.6 

15-3 
41 .6 


98.7 

72.7 

42.8 

4.0 

12.5 

34-1 

20.0 

9.8 

6.6 


9.2 


37-3 


24.9 
3-4 


S-o 


5-5 
9.2 

3-3 


14-3 


29.0 

12. 5 

3-4 


S-o 
22.5 


5-5 

9.2 

6.7 
30.0 

15-0 
12.5 
12.5 
14.0 
6.3 


5-S 
4.1 


4.6 


1-3 
4.6 


4.0 
2.  2 
1.6 

23-3 


4.0 


2.  2 

I3-I 
10. o 


Kuttner  in  a  discussion  tells  of  the  results  of  his  researches  among  old 
subjects  of  exophthalmic  goiter,  with  results  that  speak  immeasurably  in  favor 
of  the  surgical  procedure.  He  stated  that  it  was  especially  important  to 
study  the  remote  results  of  operation  in  cases  of  Basedow's  disease,  and  that 
we  should  not  consider  of  such  vital  importance  merely  the  immediate  results. 
Of  twenty-one  well-marked  cases  treated  conservatively,  none  had  recovered 
health,  nine  having  been  treated  for  a  period  of  at  least  fifteen  years,  35.7 
per  cent,  had  died,  and  only  one  was  able  to  work.  Of  the  cases  of  the 
same  series  that  were  operated  on  only  17.3  per  cent,  had  died,  and  of  those 


152  THE    DISEASES    OF    THE    THYROID    GLAXD 

living,  86.2  per  cent,  had  either  entirely  recovered  or  were  able  to  do  their 
work. 

Halsted  himself  has  done  about  650  operations  in  500  patients  with  Base- 
dow's disease.  A  one-sided  lobectomy  resulted  in  an  approximate  cure  in 
possibly  60  per  cent,  of  the  cases.  For  scientific  purposes,  to  ascertain  the 
role  of  the  thymus  in  Basedow's  disease  he  recommends  primary  thymectomy, 
or  secondary  thymectomy  where  both  lobes  of  the  thyroid  have  been 
removed  without  proper  eftect.  He  states,  however,  that  he  is  sorely  tempted 
to  remove  a  portion  of  an  enlarged  thymus  when  he  meets  with  it  in  the 
course  of  an  operation  for  Basedow's  disease. 

Kendall  has  recently  succeeded  in  obtaining  from  the  thyroid  gland  a 
substance  containing  60  per  cent,  iodine.  Apparently  it  is  di-iodo-di- 
hydroxy-indol  and  it  represents  the  main  physiologic  activity  of  the  gland. 

References 

Dutrow  (H.  v.).  Idiopathic  nonpurulent  acute  thyroiditis;  report  of  a  case  with 
complete  recovery.     Jr.  Am.  M.  Ass.,  1911,  LVIII,  p.  1761. 

Halsted  (]]'.  S.).  The  significance  of  the  thymus  gland  in  Graves'  disease.  Bulletin 
of  the  Johns  Hopkins  Hospital.  \'ol.  XXXV,  Xc.  282,  August.  1914,  pp.  223-234. 

Klose,  Lampe,  and  Licsegang.  Die  Basedowische  Krankheit  Beitrage  zur  klinischen 
Chirurgie,  XXX\TI,  1912,  p.  601-779. 

Lampe  (A.  E.).  Basedowsche  Krankheit  und  Genitale.  Untersuchungen  mit  Helfe 
des  Abderhaldenschen  Dialysierverfahren.  Monatsschrift  fiir  Geburtshilfe  und  Gj'nako- 
logie,  38,  1913.  pp.  45-51.  See  also  Lampe  and  Papazoln.  Miinch.  med.  Wchsch.,  1913; 
and  Lampe,  Fortschritte  der  naturwissenschriftlichen  Forschung,  herausgegeben  von 
E.  Abderhalden,  Bd.  9,  19 13. 

Deutsch  (H.).  Erfahrungen  mit  dem  Abderhaldenschen  Dialysierverfahren  I. 
Mitteilung.  Abbau  von  Thymusgewebe  durch  normales  Serum.  Wien.  klin.  Wchsch., 
38.  26,  1913,  pp.  1492-1493. 

Porter  (J/.  F.).  Diseases  of  the  thyroid  in  the  female.  Am.  J.  Obst.,  LXI\',  pp. 
781-790. 

Thomas  (C.  P.).  The  thyroid  gland  and  some  of  its  diseases.  International  Journal 
of  Surgery,  Vol.  XXV,  Jan.,  191 2,  pp.  6-8. 

Crile  {G.  IF.)  and  Lour r  (IF.  £.).     Anoci-Association.     W.  B.  Saunders  &  Co.,  1914. 

Crile  (G.  IF.).  The  kinetic  system.  Cleveland  M.  J.,  \'ol.  XI,  Xo.  4,  Oct.,  1913, 
p.  665.  In  connection  with  which.  Hitchins  [G.  IT'.),  Sloan  (H.  A.),  and  Austin  (J.  B.). 
Laboratory  studies  of  the  activities  of  the  brain  and  the  adrenals  in  response  to  specific 
stimuli.     Cleveland  M.  J.,  Vol.  XI,  Xo.  4,  Oct.,  1913,  pp.  684-691. 

Crile  (G.  TF.).  The  kinetic  theory  of  Graves'  disease.  Am.  J.  M.  Sc,  Xew  Series, 
\'ol.  CXLV,  Jan.,  1913,  p.  28. 

Mailer  [and  Frazier].  Discussion  of  Guthrie's  article.  Pennsylvania  ^ledical 
Journal,  Vol.  XVII,  Xo.  9.  June,  1914,  p.  687. 

Gushing  (H.).  The  pituitary  body  and  its  disorders.  J.  B.  Lippincott  Co.,  Phila., 
1912. 

Kochcr.     "Surgery  of  Thyroid"  in  Keen's  System  of  Surgery. 

Meyers  (M.  A'.).  Epilepsy  in  adult  life  in  association  with  thyroid  disease,  a  report 
of  seven  cases.  Monthly  Cyclopedia  and  Medical  Bulletin,  Vol.  V,  Xo.  5,  ^lay,  191 2, 
pp.  266-277. 


ADDENDUM  1 53 

Meyers  {M.  K.) .  Report  of  a  case  in  which  epilepsy  in  adult  life  developed  after  the 
overuse  of  thyroid-gland  extract.  Monthly  Cyclopedia  and  Medical  Bulletin,  Vol.  V, 
No.  6,  June,  1912. 

Kocher  (Th.).  Das  Blutbild  bie  Cachexia  thyreopriva  (Myxodem.  Cretinoide  Zu- 
stande).     Archiv  fiir  klinische  Chirurgie,  99,  1912,  pp.  280-303. 

Fonio  (A.).  Ueber  den  Einfluss  von  Basedowstruma  und  Kolloidstrumapraparaten 
und  Thyreoidin  auf  den  Stickstoffwechsel  und  auf  das  Blutbild  von  Myxodem,  unter 
Beriicksichtigung  ihres  Jodgehaltes.  Mitteilungen  aus  den  Grenzgebieten  der  Medizin 
und  Chirurgie,  Vol.  XXIV,  1911-1912,  pp.  123-159. 

MacCarty  {W.  E.).  Pathological  anatomy  of  goiter.  New  York  State  Journal  of 
Medicine,  Vol.  XII,  No.  10,  Oct.,  191 2,  pp.  595-599. 

Wilson  {L.  B.).  A  study  of  the  pathology  of  the  thyroids  from  cases  of  toxic  non- 
exophthalmic  goiter.  Journal-Lancet,  Minneapolis,  Vol.  XXXIV,  No.  4,  Feb.  15, 
1914,  p.  97.  Also,  the  pathology  of  the  thyroid  in  exophthalmic  goiter.  Tr.  Ass.  Am. 
Phys.,  Vol.  XXVIII,  1913,  pp.  576-586. 

Plummer  {H.  L.).  The  clinical  and  pathological  relationship  of  simple  and  exoph- 
thalmic goiter.  Am.  J.  M.  Sc,  Vol.  CXLVI,  Dec,  1913,  p.  790.  Also,  Tr.  Ass.  Am. 
Phys.,  Vol.  XXVIII,  1913,  pp.  587-594. 

Solis-Cohen  (S.).  The  nonsurgical  treatment  of  exophthalmic  goiter.  Am.  J. 
M.  Sc,  New  Series,  CXLIX,  July,  191 2,  pp.  13-20. 

Musser  (/.  H.).  Problems  in  the  treatment  of  exophthalmic  goiter.  Am.  J.  M.  Sc, 
Vol.  CXLIII,  June,  1912,  pp.  810-815. 

Abrams  {A.).  Treatment  of  exophthalmic  goiter.  International  Clinics,  Series  22, 
Vol.  IV,  1912,  pp.  35-44. 

Stoney  {F.  A.).  On  the  results  of  treating  exophthalmic  goiter  with  X-rays.  Brit. 
M.  J.,  Aug.  31,  1912,  pp.  476-480. 

Lewi  (W.  G.).  Exophthalmic  goiter  and  perverted  thyroid  secretion  and  their 
treatment  with  high-frequency  electricity.  Albany  Medical  Annals,  Vol.  XXXIV, 
No.  2,  Feb.,  1913,  pp.  63-73. 

Mayo  (C.  H.).  Diseases  of  the  thyroid.  Journal  of  the  Michigan  State  Medical 
Society,  Vol.  XI,  No.  i,  Jan.,  1912,  pp.  1-2. 

Kiittner.     [Discussion.]     Annals  of  Surgery,  Vol.  LV,  1912,  p.  148. 

Turner  (D.).  Radium  rays  in  the  treatment  of  hypersecretion  of  the  thyroid  gland. 
Lancet,  Sept.  27,  1913,  pp.  924-925. 

Marine  {D.).  Some  remarks  on  the  thyroid  gland  in  its  relation  to  Basedow's  syn- 
drome.    Cleveland  M.  J.,  Jan.,  1913,  pp.  21-29. 

Gilbride  (/.  /.).  Cultures  from  the  thyroid  gland  in  goiter;  a  bacteriological  study 
of  fourteen  cases.     J.  Am.  M.  Ass.,  LVII,  191 1,  p.  1988. 

Kendall  (£.  £.).  The  isolation  in  crystalline  form  of  the  compound  containing  iodine 
which  occurs  in  the  thyroid.     J.  Am.  M.  Ass.,  Vol.  LXIV,  No.  25,  June  19,  1915. 


CHAPTER  HI 
THE  CRETINIC  DEGENERATION 

The  enormous  social  significance  of  the  cretinic  degeneration  in  the  coun- 
tries affected  by  it  may  be  seen  by  a  glimpse  at  the  following  figures,  which 
I  take  for  the  most  part  from  the  works  of  Eivald  and  E.  BircJier.  In  Switzer- 
land 7.2  per  cent,  of  the  applicants  for  military  service  must  be  rejected  on 
account  of  goiter,  and  2  per  cent,  must  later  be  discharged.  In  Cisleithania 
there  occurred  for  every  100,000  inhabitants  71  cretins;  in  many  strongly 
infested  districts,  for  example,  in  Murrau,  in  the  Steiermark,  there  are  more 
than  1000  cretins  per  100,000  inhabitants.  In  France,  in  1873.  there  were 
about  I  per  cent,  goitrous  among  the  inhabitants  and  0.3  per  cent,  cretins 
and  idiots;  in  Piedmont  in  1883  about  0.15  per  cent,  of  cretins;  in  Lombardy 
0.2  per  cent.,  etc.  The  etiology  of  this  affection  is  not  as  yet  explained. 
The  study  of  the  geographical  distribution  shows  that  goiter,  goiter  heart, 
endemic  cretinism,  and  endemic  mutism  belong  together.  Typical  Basedow's 
disease  is  rare  in  goitrous  districts.  ^Manifestations  of  hyperthyrosis  are 
commonly  found  there  combined  with  those  of  goiter  heart.  The  parallelism 
in  the  distribution  of  endemic  mutism  with  that  of  endemic  cretinism  is 
convincingly  shown  by  the  investigations  of  BircJicr  for  Switzerland,  and  the 
statistics  of  v.  Wagner  for  Austria.  For  lower  France,  there  are  the  observa- 
tions of  Lobenhojfcr.  The  group  relationship  of  goiter  and  endemic  cretinism 
is  seen  not  only  in  the  fact  that  the  cretins  are  almost  always  goiter  carriers, 
but  also  through  the  almost  unexceptional  occurrence  of  goiters  in  the  ancestry 
of  the  cretins.  This  and  other  established  facts  point  to  a  common  etiological 
factor  in  the  different  forms  of  the  cretinic  degeneration.  As  to  this  all  ob- 
servers agree.  On  the  contrary,  there  is  as  yet  no  agreement  as  to  the  ques- 
tion whether  the  manifold  manifestations  of  the  cretinic  degeneration  are 
called  into  existence  only  by  the  mediation  of  the  strumous  degeneration  of 
the  thyroid  gland,  or  whether  a  part  of  these  are  directly  produced  by  the 
strumous  noxus  and  thus  are  coordinate  with  the  struma. 

The  cretinic  degeneration  is  found  in  Europe  especially  in  the  central 
Alps;  large  goitrous  districts  exist  in  addition  in  the  Carpathians,  the  German 
middle  mountains,  and  the  Pyrenees.  In  the  other  parts  of  the  earth,  also, 
the  goiter  districts  lie  in  mountainous  districts.  The  goiter  districts  change; 
localities  that  were  formerly  infested  become  goiter-free,  and  conversely. 
Sometimes  there  occurs  an  epidemiform  breaking-out.  When  the  affection 
retrogresses  in  one  district,  first  the  most  severe  forms  of  the  cretinic  degenera- 
tion disappear  for  the  most  part,  while  the  goiter  alone  remains  for  some  time 

154 


GOITER  155 

(for  example,  in  Baden  and  Thiiringen).  Persons  who  come  from  a  nongoi- 
ter  neighborhood  into  a  goiter  neighborhood  often  develop  goiter,  or  become 
affected  with  it  after  their  return.  E.  Bircher  here  cites  an  instructive  ex- 
ample. A  family  in  a  nongoiter  neighborhood  had  healthy  children.  When 
they  came  into  a  goiter  district,  the  parents  themselves  remained  non- 
goitrous  but  had  a  cretin  for  a  child.  Kocher  reports  another  example:  The 
parents  were  healthy,  and  as  long  as  they  lived  in  a  goiter-free  district  had 
nine  healthy  children.  When  they  came  into  a  goiter  district,  they  had  three 
cretin  children,  of  which  the  first  was  the  most  pronouncedly  affected. 
Again  the  thirteenth  child  was  normal,  but  very  small.  Breitner  has  recently 
published  a  similarly  instructive  case.  Enormous  outbreaks  of  goiter  have 
been  often  observed  in  regiments  after  their  stationing  in  goiter  districts. 
Families  that  remove  from  goiter  districts  can  soon  lose  their  goiters.  Also 
the  occurrence  of  goiters  is  not  rarely  observed  in  animals,  after  their  trans- 
ference to  a  goiter  district. 

The  noxus  of  goiter  is  bound  in  the  drinking  water.  In  the  goiter  terri- 
tories there  exist  indeed  especial  goiter  brooks;  there  are  numerous  examples 
in  the  literature  of  goiter  communities  becoming  free  of  goiter  after  they 
had  established  drinking-water  conduits  from  goiter-free  vicinities. 

The  occurrence  of  the  goiter  noxus  in  the  water  is  bound  together  with  a  definite 
geological  structure  of  the  soil.  This  view  has  been  especially  promulgated  by  Bircher, 
Jr.,  on  the  ground  of  his  penetrating  studies  and  excellent  observations.  According  to 
Birc/ier.  cretinic  degeneration  is  found  only  upon  the  marine  deposits  of  the  paleozoic 
ages,  the  dryassic.  and  the  tertiary  ages,  while  the  eruptive  formations,  the  Jurassic  and 
fresh-water  deposits,  are  free  from  the  noxus.  This  view  is  not  generally  shared,  but  is, 
however,  set  upon  a  working  basis  by  the  works  of  Johannesen,  and  latterly  by  Bircher, 
Jr.,  and  Lobenhofer.  The  practical  significance  of  the  investigations  of  Bircher,  Sr., 
is  seen  at  its  best  in  that  the  community  Rupperswill  has  become  goiter-free  since  it 
has  led  its  water  from  springs  lying  in  Jurassic  deposits.  A  like  example  is  furnished  by 
the  ^dllage  Asp. 

Previously  healthy  animals  may  become  goitrous  on  having  goiter  water 
furnished  to  them.  The  noxus  goiter  goes  through  a  Berkefeld  filter;  it  is 
destroyed  by  temperature  higher  than  yo^C.  (E.  Bircher).  Therefore  it  is 
likely,  as  Wilms  first  assumed,  that  the  noxus  is  not  a  miasma,  but  a  toxin  or 
toxalbumin  from  an  organic  substance. 

It  does  not  dialyze,  therefore  behaving  like  a  colloidal  emulsion.  The 
struma  produced  shows  histologically  changes  that  are  degenerative,  and  on 
the  use  of  weaker  goiter  water,  also  h^-perplastic.  The  animals  developed 
cardiac  hj-pertrophy,  and  many  remained  behind  in  growth. 

I.  Goiter 

We  understand  by  this  term  a  noninflammatory,  diseased  alteration  of  the 
ihvroid.  mostlv  associated  nitJi  oilar'jenient  of  this  pland,  nJiile  the  thvroid  in 


156  THE    CRETINIC    DEGENERATION 

most  cases  shows  hyperplastic  manifestations,  and  alicays  degenerative  manifes- 
tations. The  hyperplasia  may  affect  the  parenchyma  as  well  as  the  vessels. 
The  degenerative  nature  of  the  alteration  is  seen  in  the  fact  that  the  h}T3er- 
plasia  of  the  parenchyma  is  for  the  most  part  unaccompanied  with  increase  in 
function.  Therefore  either  the  parenchyma  must  be  less  capable  of  function- 
ating or  the  giving  off  of  secretion  is  hindered  by  the  sclerotic  process.  For 
the  most  part  there  is  found  sufficient  parenchyma  capable  of  functionating. 
According  to  the  stronger  or  weaker  participation  of  the  hyperplastic  or  de- 
generative processes  we  distinguish  parenchymatous,  vascular,  or  fibrous — 
further,  diffuse  or  circumscribed- — goiters;  when  the  stagnation  of  the  secretion 
is  greater,  we  have  colloid  or  cystic  goiters.  In  goiter  neighborhoods  there 
also  occur  hyperplastic  congenital  goiters.  There  seems  to  exist  a  certain 
relationship  between  goiter  and  myomata  of  the  uterus.  At  least  it  has  been 
observed  that  in  strumous  women  who  also  suffer  with  myomata,  the  struma 
also  decreases  in  size  with  the  retrogression  of  the  myoma  at  the  menopause 
(Ullmann).  Concerning  the  further  distinctions,  the  differential  diagnosis, 
and  the  surgical  treatment,  I  shall  refer  [the  reader]  to  v.  Eiselsherg  s  mono- 
graph. Among  the  nonsurgical  methods  of  treatment,  I  mention  only  the 
iodine  treatment.  This  is  the  more  eft"ective  the  more  the  hyperplastic  altera- 
tions and  the  less  the  degenerative  alterations  are  present.  That  in  certain 
neighborhoods  iodine  therapy  often  leads  to  manifestations  of  hyp2rthyrosis 
has  already  been  mentioned  in  detail  in  the  chapter  on  Basedow's  disease. 
The  thyroid  therapy  recommended  by  v.  Brims  is  less  used  nowadays. 
Not  much  can  be  expected  from  the  treatment  of  ordinary  goiter  by  the 
X-rays. 

2.  Goiter  Heart 

The  coincidence  of  goiter  and  cardiac  disturbance  is  very  common.  The 
statistics  of  Schranz,  which  are  based  on  an  investigation  of  two  hundred  and 
sixty-four  goitrous  school  children,  one  hundred  and  seventeen  goitrous  adults, 
and  seven  hundred  and  twenty  autopsy  protocols  of  the  Innsbruck  Patho- 
logico-anatomical  Institute,  show  that  after  subtraction  of  the  valvular  de- 
fects, 23  per  cent,  of  the  children  and  49  per  cent,  of  the  adults  suffered  from 
heart  trouble.  Of  the  autopsied  cases  one  hundred  and  eighty-eight  showed 
degenerative  alterations  of  the  cardiac  muscle,  some  with  hypertrophy. 
While  these  figures  can  only  partially  stand  ground  against  criticism  (Wolfier, 
Fr.  Kraus,  Minnich)  they  are  indeed,  even  when  reduced,  sufficient  to  show 
the  common  coincidence  of  goiter  and  cardiac  disturbances.  Rose  showed,  be- 
fore Schranz,  that  the  stagnation  [congestion]  in  the  lesser  circulation  caused 
by  the  large  goiter  can  lead  to  dilatation  and  insufficiency  of  the  right  heart 
(so-called  Rose's  goiter  heart).  When  the  embarrassment  to  respiration  on 
account  of  the  goiter  enters  more  into  the  foreground  we  call  the  condition, 
following  the  lead  of  Kocher,  pneumonic  goiter  heart.     Conversely,  primary 


GOITER    HEART  157 

stagnation  in  the  lesser  circulation  may  lead  to  enlargement  of  the  thyroid 
gland  with  greater  or  less  manifestations  of  hyperthyroidism  [Revilloid's 
''goitre  cardiaque''). 

Revilloid  already  mentioned  that  slight  manifestations  of  hyperthyroid- 
ism may  occur  with  this  ''goitre  cardiaque."  This  was  later  made  intelligible 
by  the  experiments  of  Blum  which  showed  that  ligation  of  the  thyroid  veins 
leads  to  an  eddying  out  of  the  thyroid-gland  secretion  and  therewith  to  a 
slight  hyperthyrosis.     Later,  cirrhotic  changes  occur  in  such  thyroids. 

Fr.  Kraus  first  mentioned  that  there  were  numerous  cases  of  cardiac  dis- 
turbances in  goiter  in  which  all  stagnation  is  absent,  and  in  which,  therefore, 
the  mechanical  factor  as  a  cause  does  not  come  into  consideration.  In  the 
light  forms  of  these  are  found  tachycardia,  often  dicrotism  of  the  pulse,  slight 
strengthening  of  the  apex  impulse,  beating  of  the  carotids,  sometimes  arrhyth- 
mia, glittering  eye,  sometimes  indeed  a  slight  degree  of  exophthalmus,  in- 
clination to  sweating,  trembling,  and  eventually  slight  heightening  of  the 
fundamental  exchange,  in  short  phenomena  of  a  slight  hyperthyrosis.  In  the 
severer  forms  are  found,  in  addition,  hypertrophy  and  dilatation  of  the  heart 
and  degenerative  changes  in  the  cardiac  muscle.  Also  v.  Mukulicz  and 
Reinhach  found  similar  symptoms  in  a  great  percentage  of  the  goitrous  that 
they  examined. 

The  fact  that  hypertrophy  and  premature  degeneration  of  the  cardiac 
muscle  is  found  so  frequently  in  the  goitrous  with  cardiac  disturbances  indi- 
cates that  we  are  here  not  dealing  with  the  ordinary  forms  of  hyperthyroid- 
ism. Fr.  Kraus  first  championed  the  greater  nosological  independence  of  this 
form;  the  newer  investigation,  results  of  Minnich  and  E.  Bircher  seem  fully 
to  corroborate  his  contention.  The  opinions  of  Minnich,  in  his  significant 
monograph,  in  so  far  as  he  regards  these  Basedow's  manifestations  as  the 
expression  of  a  diminished  thyroid-gland  function,  are  not  shared  by  the 
author.  Entirely  new  views,  however,  are  opened  by  Minnich  in  his  descrip- 
tion of  cardiac  disturbances  in  relatively  young  strumous  individuals  of 
both  sexes,  which  mostly  set  in  with  new  impulses  in  the  growth  of  the  goiter 
and  lead  objectively  to  enlargement  of  the  heart,  eventually  with  the  gradual 
development  of  a  protrusion  of  the  precordium,  and  frequently  also  of 
accidental  murmurs  and  subjectively  to  pains  in  the  cardiac  region,  pricking 
pains,  pressure,  painful  precordial  points  of  tenderness,  and  cardiac  palpita- 
tions. Such  cases  may  remain  stationary  a  long  time,  or  even  become  cured, 
or  they  may  go  over  into  tachycardia.  This  was  the  case  in  eleven  of  twenty 
cases.  Here,  therefore,  we  are  dealing  with  a  form  of  goiter  heart  in  which, 
at  least  in  the  beginning,  hyperthyroidal  symptoms  were  hardly  present. 

The  fundamental  significance  of  these  observations  is  supported  by  the 
experiments  of  E.  Bircher.  Bircher  saw  enlargement  of  the  heart  almost 
regularly  in  the  animals  in  which  he  artificially  induced  struma  by  giving 
them  goiter  water  to  drink.     The  weight  of  these  hearts  averaged  one-third 


158  THE    CRETINIC    DEGENERATION 

more  than  that  of  the  hearts  of  the  control  animals.  The  heart  muscle 
microscopically  for  the  most  part  showed  degenerative  changes.  B  ire  her 
refers  the  cardiac  damage  directly  to  the  goiter  noxus  ,and  in  agreement 
with  Minnieh  sees  in  it  a  disease  sui  generis. 

According  to  a  personal  communication  from  Prof.  ScJiolz  also  the  endemic 
cretins  usually  have  bad  hearts,  but  no  hypertrophy;  this  fact  may  hang  to- 
gether with  the  gradually  and  long-continued  action  of  the  goiter  noxus,  per- 
haps also  with  the  sHght  "expressions  of  hfe"  [Lebensausserungen]  of  such 
individuals. 

3.  Endemic  Cretinism 

Symptomatology. — The  habitus  of  endemic  cretinism  shows  a  much 
greater  multiformity  than  that  of  sporadic  cretinism.  Dieterle  compares 
the  photographs  of  seven  youthful  cretins  of  eighteen  years  of  age  from  Bern 
with  that  of  sporadic  cretins  from  fourteen  months  to  twenty-one  years  of 
age,  and  shows  that  despite  the  fact  that  the  latter  come  from  different 
countries,  they  show  much  similarity  to  one  another,  while  the  others  re- 
semble one  another  less  strongly  although  they  come  from  the  same  family. 
Dieterle  cites  the  doctrine  of  Majfeis,  that  there  is  no  cretinic  prototype. 
The  skulls,  too,  in  endemic  cretinism  show  greater  differences;  in  many 
endemic  cretins  the  skull  is  small,  the  forehead  low  and  receding;  in  others  the 
skull  is  abnormally  large.  Regularly  the  root  of  the  nose  is  retracted,  al- 
though never  to  so  great  a  degree  as  in  chondrodystrophy;  for  the  most  part 
the  eyes  stand  wide  apart,  the  throat  is  short  and  thick,  the  lips  are  cushiony, 
the  facial  expression  morose.  Ordinarily  the  skeleton  shows  abnormalities 
— ankyloses,  scolioses,  etc.  ScJiolz  describes  flattening  of  the  head  of  the 
femur.  The  pelvis  is  often  narrowed  in  all  dimensions,  and  the  bones  are 
provided  with  swellings  [Wiilsten].  Also  there  is  difference  in  the  degree  of 
dwarfism,  v.  Wagner  observed  individuals  under  90  cm.,  although  there 
are  full  cretins  over  150  cm.  in  body  length.  E.  Bircher  of  Aarau  has  kindly 
provided  me  with  Figs.  18-22.  Fig.  18  shows  the  multiformil}'  of  the  facial 
expression  and  the  shape  of  the  skull  in  endemic  cretinism. 

The  duration  of  life  of  the  cretins  is  in  most  cases  shortened,  yet  some 
cretins  attain  a  very  high  age.  Kocher  reports  about  seventy-year-old  and 
even  one-hundred-year-old  cretins. 

The  figure  is  awkward,  the  gait  inelastic,  the  muscles  are  poorly  developed; 
individuals  with  completely  developed  forms  can  indeed  not  walk,  but  can 
only  creep.  This  depends,  however,  not  as  much  on  the  muscular  weakness 
as  on  the  want  of  every  fine  coordination.  The  skin  of  the  face  is  often  very 
lax,  numerous  transverse  wrinkles  traverse  the  forehead  and  lend  to  the 
face  an  old  appearance.  The  development  of  the  myxedema  is  very  diverse. 
Magnus-Levy  and  v.  Wagner  found  in  many  cases  typical  supraclavicular 
pseudolipomata,  and  also  on  other  places  of  the  skin  very  evident  pad-like 


ENDEMIC    CRETINISM 


159 


swelling  and  myxedematous  alteration  of  the  mucous  membrane.  Scholz 
found  the  skin  only  atrophic.  In  60  per  cent,  of  the  cases  investigated  by 
E.  Bircher  the  myxedematous  swelling  of  the  skin  was  absent.  There  are 
also  cases  that  sweat  profusely.  The  hairs  are  for  the  most  part  short  and 
bristly,  the  nails  torn,  the  teeth  defective,  the  hair  in  the  axillge  and  on  the 
pubes  may  be  absent  or  only  sparsely  developed.  UmbiHcal  hernia  in  chil- 
dren as  well  as  obstipation  and  distention  of  the  abdomen  is  just  as  frequent 
as  in  sporadic  cretinism.     Often  conjunctivitides  are  found,  and  as  a  result 


Fig.   18. — Group  of  endemic  cretins  from  Aarau. 


of  these,  eczema  of  the  palpebral  borders.  According  to  Hitschmann,  the 
conjunctivitides  probably  develop  through  disturbance  in  the  leading  off  of 
the  tears  on  account  of  the  saddle  nose.  There  mostly  occurs  a  fairly  high 
degree  of  anemia.  The  disturbances  of  intelligence  of  the  cretins  may  vary 
from  the  slight  grades  of  feeble-mindedness  up  through  all  the  grades  to  the 
failure  of  all  mental  expression — the  so-called  plant  man.  In  such  cases 
all  development  of  speech  is  also  absent.  In  most  cases,  however,  some  psy- 
chical development  is  still  present.     The  perception,  however,  is  somewhat 


i6o 


THE    CRETIXIC    DEGENERATION 


slowed,  the  memory  very  poor ;  as  for  the  emotions,  the  cretins  show  a  certain 
clinging  for  the  persons  who  feed  them  or  hate  against  those  whom  they 
regard  as  enemies. 

The  pathologico-anatomical  findings  in  the  brains  of  cretins  are  very  di- 
verse. Often  they  are  only  trivial;  in  most  cases,  however,  there  are  found 
several  alterations,  and  these  of  greater  intensity.  ScJiolz  and  Zingerle 
found  at  times  chronic  meningitic  alterations  and  a  slight  grade  of  hydro- 


FiG.   ig. — Endemic  cretinism.  FiG.   20. — Cretins  with  mj-xedematous  facial  expression. 

cephalus.  The  brain  may  be  smaller  in  toto — or  in  individual  lobes;  often  it 
is  highly  asymmetric,  sometimes  there  is  found  a  persistence  of  the  juvenile 
developmental  stages,  or  in  rare  cases  excessive  development.  The  dis- 
turbances of  development  may  affect  the  hemispheres  as  well  as  the  brain- 
stem, the  cerebellum,  etc.  The  confirmation  of  the  surface  of  the  brain 
is  often  pathologically  aftected  in  that  the  convolutions  are  smaller  or  their 
nurnber  lessened.  In  abnormally  small  brains  of  cretins  it  may  well  be  sup- 
posed that  the  smallness  of  the  brain  is  primary,  that  of  the  skull  secondary; 


ENDEMIC    CRETINISM 


i6i 


as  Bourneville  taught  of  idiots'  brains.  The  brain  substance  of  cretins,  accord- 
ing to  Scholz  and  Zingerle,  is  often  strikingly  compact,  the  amount  of  gray 
matter  [relatively]  exceeding  in  mass  the  white. ^  The  disturbances  of  de- 
velopment may  affect  different  parts  in  very  different  ways.  The  inhibition 
of  the  development  of  the  sense  organs  is  certainly  to  be  ascribed,  in  part,  to 
■  the  faulty  development  of  the  central  organs. 

The  nervous  status  commonly  shows  increase  of  the  reflexes,  according  to 
Scholz  in  52  per  cent.;  the  field  of  vision  was  found  by  Ottolenghi  to  be  re- 
stricted, especially  outward  and  upward.  Hitschmann  found  the  eye 
grounds  normal  in  nearly  all  his  cases;  only  in  certain  cases  were  crescents 
directed  downward  found,  relationship  of  which  with  the  cretinic  degener,a- 
tion  was  entirely  obscure.  The  testing  of  sensibility,  of  the  sense  of  taste  and 
smell,  naturally  presents  great  difficulties. 


Fig.  21. 


Fig.  22. 


-TIG.  21.  i^iG.  22. 

Figs.  21  axd  22. — Cretins  with  myxedematous  facial  expression. 

The  disturbances  of  hearing  are  of  very  diverse  degrees.  In  many  cases, 
the  power  of  hearing  is  fully  intact.  In  others,  there  exists  a  slight  or  severe 
grade  of  hardness-of-hearing  or  mutism.  Frightfully  large  is  the  number  of 
mutes  who  are  completely  deaf. 

Endemic  Mutism. — In  all  countries  in  which  cretinism  is  endemic  there 
is  found  a  large  number  of  deaf-mutes.  According  to  the  older  statements 
of  St.  Lager,  Switzerland  possesses  five  thousand  cretins  and  four  thousand  deaf- 
mutes.  To  the  latter,  of  course,  belong  some  cases  of  sporadic  mutism,  that  is, 
those  which  depend  on  a  meningitis  in  earliest  youth,  on  otitides  or  formation 

^  I  have  here  rectified  the  author's  error  by  reference  fo  Scholz  and  Zingerle's  article.     The 
German  text  here  transposes  "white"  and  "gray." — Editor. 
II 


1 62  THE    CRETINIC    DEGENERATION 

anomalies  of  the  brain,  and  which  have  nothing  to  do  with  the  goiter  noxus.  A 
very  great  number,  however,  belong  to  endemic  cretinism  (according  to 
E.  Bircher,  80  per  cent,  in  Switzerland).  Also  in  Austria,  and  especially  in 
the  Stiermark,  are  found  an  enormous  number  of  deaf-mutes.  Scholz  found 
among  the  cretins  examined  by  him  29  per  cent,  deaf-mutes  and  32  per  cent, 
hard-of-hearing.  The  intensity  of  the  disturbance  of  hearing  does  not  go 
parallel  throughout  with  that  of  the  remaining  cretinic  symptoms.  There 
are  complete  cretins  that  show  only  slight  disturbances  of  hearing  and  speech. 
In  others  the  mutism  may  be  the  chief  symptom  of  the  cretinic  degeneration 
(larval  form  of  i'.  Eiselsberg). 

The  statements  as  to  the  functional  disturbances  or  the  pathologico- 
anatomical  findings  in  the  deaf  cretins  and  in  the  endemic  deaf-mutes  diverge 
greatly.  Hammerschlag,  whom  we  have  to  thank  for  the  first  exact  investiga- 
tions, found  on  the  one  hand  alterations  in  the  peripheral  hearing  apparatus, 
and  on  the  other  only  disturbance  of  the  perception  of  sound,  as  also  found 
Scholz,  Frdschel,  and  others.  Further,  there  was  found  in  endemic  cretinism 
incomplete  ossification  of  the  stapes,  inhibition  of  development  of  the  epi- 
thelial cells  in  the  ductus  cochlearis  {Habermann,  Alexander),  shortening  of 
the  base  of  the  skull  and  thereby  disturbance  in  the  development  of  the  organ 
of  hearing  {Danzinger,  Bircher) ,  incomplete  ossification  of  the  organ  of  hearing 
with  hyperostotic  growths  at  other  plages  {Moos  and  Steinhrugge).  Anom- 
alies of  the  malleus  {Nager),  myxedematous  thickening  of  the  tympanic 
mucous  membrane,  etc.,  have  been  regarded  as  the  cause  of  the  hardness- 
of-hearing.  Recently,  E.  Bircher  has  strenuously  criticised  a  portion  of  these 
findings  or  their  significance.  To-day  we  may  safely  assume  that  we  may 
ascribe  great  importance  to  the  degeneration  in  the  cortical  centers  or  the 
developmental  inhibitions  in  the  cortical  centers,  and  that  the  different  altera- 
tions are  directly  elicited  by  the  goiter  noxus  and  are  coordinated  with  an 
insufiiciency  of  the  thyroid,  which  finally  sets  in  (Pineles). 

The  inhibition  of  the  development  of  speech  in  endemic  cretinism  is  extra- 
ordinarily different  [in  degree];  where  hearing  is  entirely  absent,  of  course, 
the  development  of  speech  is  also  absent.  We  do,  however,  see  cases  in 
which  in  spite  of  high-grade  disturbances  of  hearing  only  relatively  slight 
defects  of  intelligence  are  present.  Of  course,  in  these  cases  articulation  is 
poor  (Hammerschlag) .  In  other  cases,  in  spite  of  good  hearing,  intelligence 
and  the  development  of  speech  are  minimal.  Here  also  we  assume  a  de- 
velopmental inhibition  of  cortical  centers  {Scholz  and  Zingerle).  Where 
the  endemic  shows  less  intensity,  defects  of  intelligence  may  be  entirely 
absent  {H.  Bircher). 

Investigations  as  to  the  metabolism  in  endemic  cretins  have  been  pub- 
lished only  by  Scholz.  Scholz  designates  the  metabolism  as  very  sluggish. 
The  amounts  of  urine  were  very  slight,  as  well  as  the  exchange  of  protein  and 
of  salts.     The  excretion  of  nitrogen,  uric  acid,  creatinin,  and  sodium  chloride 


ENDEMIC    CRETINISM  1 63 

was  very  slight,  and  that  of  urea,  the  xanthin  bases,  ammonia,  and  sulphuric 
acid  showed  corresponding  proportions.  There  was  further  noted  a  tendency 
to  retention  of  phosphorus  and  nitrogen.  The  metabohsm  therefore  shows 
a  relation  analogous  to  that  in  myxedema.^  Very  interesting  are  the  results 
of  feeding  with  thyroid  gland.  Diuresis  increases.  The  nitrogen  elimination 
was  not,  however,  essentially  influenced,  while  the  body  weight  diminished. 
Therefore  chiefly  nitrogen-free  substances  must  be  consumed. 

As  the  cretins  investigated  showed  no  distinct  myxedematous  swellings, 
it  was  not  to  have  been  expected  that  the  initial  increase  of  the  protein 
combustion  observed  in  myxedema  would  be  present.  The  experiments 
all  show  that  the  depressed  protein  exchange  in  endemic  cretinism  cannot  he 
stimulated  so  easily  as  in  myxedema.  I  cannot  see  in  this  an  analogy  to 
Basedow's  disease,  as  Scholz  does,  as  the  absence  of  a  further  increase  of 
nitrogen  elimination  through  thyroid  substance  in  Basedow's  disease  may 
have  its  ground  in  the  circumstance  that  the  excess  of  thyroid-gland  secretion 
does  not  come  distinctly  into  action,  if  in  higher  grades  of  hyperthyrosis  the 
energy  of  the  protein  decomposition  has  reached  a  great  intensity.  Scholz 
further  observed  in  his  experiments  that  under  the  influence  of  administra- 
tion of  thyroid  gland,  the  calcium  in  the  urine  decreases  markedly  and  in- 
creases in  the  feces,  as  we  have  also  observed  in  normal  individuals.^ 

For  the  most  part  there  is  found  in  cretins  a  fairly  evident  hypoplasia  of 
the  genitalia.  In  women  the  labia  and  the  uterus  are  mostly  small,  but  it 
may  happen  that  the  external  genitalia  are  relatively  well  developed;  the 
ovaries  are  small  and  often  show  small  cystic  degeneration;  the  menses  are 
absent  or  are  scanty  and  irregular;  the  mammae  are  poorly  developed  and  with- 
out glandular  tissue.  In  men  the  penis  is  often  very  small,  the  testicles  are 
not  well  descended,  and  on  microscopical  examination  show  spermatozoa 
very  sparingly.  The  scrotum  is  lax.  In  both  sexes  the  secondary  sexual 
characters  are  for  the  most  part  very  defectively  developed;  the  sexual  in- 
stinct is  entirely  absent  or  is  very  weak  only;  in  many  a  light  case,  however, 
procreative  power  and  conception  are  observed.  E.  Bircher  reports  con- 
cerning a  cretin  of  the  most  severe  grade  who  conceived;  the  fetuses,  how- 
ever, are  not  capable  of  living,  even  when,  as  in  a  case  of  Eppinger,  they  show 
no  sign  of  cretinic  degeneration.  The  genitalia  can,  however,  like  ossifica- 
tion, still  show  a  late  development. 

Worthy  of  observation  are  Schdnemann's  investigations,  which  show  that 
in  neighborhoods  where  goiter  is  endemic  strumous  alterations  are  found 
very  commonly  in  the  glandular  part  of  the  hypophysis.  Among  one  hundred 
twelve  cases,   the  hypophysis  was  normal  in  only   twenty-seven.     These 

1  "Not  however  to  experimental  athyrosis  proper."  This  statement  of  Scholz  is  unintelligible 
to  me,  as  according  to  my  knowledge,  an  essential  difference  between  the  metabolism  of  myxe- 
dema and  that  of  cachexia  thyreopriva  does  not  exist. 

2  See  the  chapter  on  hyperthyroidism. 


164  THE    CRETINIC    DEGENERATIOX 

persons  did  not  have  a  goiter.  Among  the  cases  with  goiter,  there  was  only- 
one  in  whom  was  found  a  h}^ophysis  that  could  be  regarded  as  probably 
normal.  "In  persons  with  struma  of  the  thyroid,  there  was  always  found 
enlargement  of  the  h}'pophysis,  and  indeed  either  proliferation  of  the  con- 
nective stroma,  also  chromophilic  strumas,  strumas  with  especially  vascular 
development  of  the  stroma  and  hyaline  degeneration  and  swelling  up  of  the 
columns  of  cells,  and  finally  those  with  marked  colloid  formation."  v.  Cyon 
found  strumous  alterations  of  the  hy'pophysis  very  frequently  in  Bernese 
dogs.     TJie  goiter  poison  therefore  works  deleteriously  on  the  hypophysis. 

As  in  sporadic  cretinism,  the  disturbance  in  bone-growth  consists  of  delay 
in  the  epiphysial  closures  and  in  retarded  appearance  of  the  bone-nuclei. 
Langhans  first  described,  in  the  skeletons  of  five  cretins,  the  remaining  behind 
in  the  ossification  and  commented  that  also  the  cretinoids  show  a  similar, 
although  less  marked,  remaining  behind.  "The  bones  previously  laid  out  in 
cartilage  grow  slowly  in  their  length;  the  epiphyses  remain  low,  the  boundaries 
of  ossification  progress  very  slowly,  the  nuclei  of  ossification  in  the  epiphyses 
occur  very  late,  and  the  epiphysial  discs  are  retained  for  long  beyond  the 
normal  term.  Remnants  of  these  discs  are  still  to  be  found  in  the  forty-fifth 
year."  v.  Wyss  has  confirmed  the  observations  of  Langhans  by  means  of  the 
X-ray  examination  of  numerous  cretins  and  cretinoids — ^and  incidentally  has 
finally  contradicted  the  previous  view  that  in  cretins  premature  ossification 
of  the  epiphysial  junctures  occurs.  This  delay  in  the  epiphysial  closure 
makes  intelligible,  as  v.  Wyss  emphasizes,  the  former  observations  of  v. 
Wagner  that  in  endemic  cretins,  even  in  late  life,  the  growth  in  height  may  go 
on.  To  this  extent  the  disturbance  in  the  ossification  agrees  fully  with  that 
in  sporadic  cretinism,  although  on  the  other  hand  there  are  dift'erences  that 
are  important  from  the  point  of  view  of  differential  diagnosis.  Already 
V.  Wyss  pointed  out  that  the  retardation  in  the  ossification  for  the  most  part 
lasts  only  a  few  years,  so  that  only  rarely  are  the  epiphysial  junctures  found 
to  be  open  after  the  twenty-fifth  year. 

Dieterle  mentions  especially  the  extensive  difference  from  thyroaplasia  in 
this  behavior  of  the  epiphysial  junctures,  which  in  thyroaplasia,  if  thyroid 
therapy  be  not  introduced,  often  remain  open.  In  youthful  age  in  endemic 
cretinism,  however,  the  remaining  of  the  ossification  behind  that  of  the  normal 
individual  is  not  inappreciable.  Dieterle  publishes  a  very  instructive  table 
in  which  he  compares  the  ages  of  the  cretins  of  v.  Wyss  as  estimated  from  the 
radiograms  of  the  hands  with  the  actual  ages  of  the  individuals.  He  finds  in 
eleven  cretins  between  the  ages  of  seven  and  eighteen  years  a  remaining 
behind  of  ossification  of  from  three  to  seven  years.  Breus  and  Kolisko 
state  moreover  that  in  six  of  the  cretin  skeletons  examined  by  them  never  did 
all  the  epiphysial  junctures  remain  open  until  an  advanced  age,  therefore 
there  did  not  exist  in  all  bones  the  same  degree  of  disturbance  of  growth,  and 
that  there  resulted  from  this  a  disproportioned  skeleton;  the  extremities  are 


ENDEMIC    CRETINISM  1 65 

slender  but  shortened  near  the  trunk,  and  there  exists  in  this  respect  a  differ- 
ence between  the  cretinic  dwarfism  and  the  true  dwarf  described  by  A.  Pal- 
fauf,  in  which  all  epiphysial  closures  remain  behind,  in  like  manner,  as  in  a 
former  child  stage  of  development.  In  those  cases  of  endemic  cretinism  in 
which  the  epiphysial  closures  are  already  ossified,  thyroid  therapy  can  natu- 
rally no  longer  lead  to  growth  in  height. 

E.  Bircher  has  recently  studied  the  disturbances  in  growth  in  endemic 
cretinism  in  a  large  number  of  cases  (fifty-six)  and  has  come  to  the  same 
results  as  Br  ens  and  Kolisko.  The  inhibition  of  the  ossification  aft"ects 
only  the  age  of  development.  After  thirty  years  of  life  the  epiphyses  and 
synchondrosis  were  found  open  only  exceptionally.  Also  Bircher  found 
throughout  that  the  inhibition  in  the  individual  bones  is  quite  dissimilar 
and  leads  to  a  disproportioned  skeleton.  Xot  rarely  E.  Bircher  found  a 
coxa  vara  or  a  humerus  varus. 

Of  quite  a  manifold  nature  are  the  findings  as  to  the  teetli  of  cretins. 
Kranz  examined  thirty  cretins  from  the  Knittelfeld  Institute  in  Steiermark 
as  to  jaw  and  tooth  formation,  and  found  numerous  anomalies  of  the  jaws, 
retarded  teething,  and  factors  giving  rise  to  anomalies  of  the  position  of 
the  teeth.  Further  he  commonly  found  alterations  of  the  structure,  de- 
fects of  the  enamel,  hxpoplasias  and  erosions  and  very  frequently  caries. 
That  these  anomalies  were  not  produced  by  the  experimental  extirpation  of 
the  thyroid  gland  in  animals  is  made  intelligible  by  the  conception  that 
athyrosis  or  hypothyrosis  and  endemic  cretins  are  different  conditions. 

Very  frequently  statements  are  made  that  endemic  cretins  are  anemic; 
with  this  agrees  the  fact  that  Langhans  found  in  a  grown  cretin  much  fat 
marrow  and  little  functioning  marrow  in  the  long  bones.  I  was  unable  to 
find  statements  as  to  the  leucocytic  formula  in  endemic  cretinism.  Mc- 
Carisson,  however,  reports  on  the  basis  of  over  one  hundred  blood  examina- 
tions in  endemic  goiter  a  regular  increase  of  lymphocytes  and  in  most  cases 
h^pereosinophilia. 

The  statements  as  to  the  thyroid  gland  in  endemic  cretins  vary  greatly. 
V.  Wagner  found  not  a  single  normal  thyroid  in  inspection  of  the  neck  of  two 
hundred  cretins.  Very  commonly  the  thyroid  is  not  palpable,  but  very  little 
value  can  be  ascribed  to  this  statement.  In  the  most  cases  are  found  goitrous 
degeneration  with  atrophy.  DeCoulon  found  in  the  thyroid  gland  of  five 
cretins,  who  died  at  the  age  of  twenty-six  to  thirty  years,  very  little  normal 
thyroid-gland  parenchyma.  One  of  these  cases  was  fairly  well  developed 
mentally.  Hanau  examined  three  thyroid  glands  that  all  were  small  and 
showed  a  marked  disappearance  of  the  parenchyma.  Also  Bayon  and  Get- 
zoiva  found  high-grade  degenerative  processes,  marked  diminution  of  the 
functionating  parenchyma,  and  enormous  development  of  hyaline-degener- 
ated connective  tissue.  Getzowa  found,  however,  similar  alterations  also  in 
the  thyroids  of  idiots  and  microcephalics  who  did  not  show  dwarfism.     On  the 


1 66  THE    CRETIXIC    DEGENERATION 

other  hand.  Bircher,  Sr.,  found  abundant  normal  thyroid-gland  tissue  in  the 
thyroid  gland  of  one  of  the  cretins  that  he  operated  on.  Recently  E.  Bircher 
reports  on  the  examination  of  over  sixty  cretins'  thyroids,  obtained  at 
autopsy  or  at  operation.  Degenerative  processes  were  present  in  all,  but 
were  of  extremely  varying  intensity,  which  often  did  not  run  parallel  with  the 
intensity  of  the  affection.  In  all  thyroids  moreover  were  found  large  por- 
tions of  normal  thyroid-gland  tissue.  E.  Bircher  found  similar  conditions  in  a 
series  of  endemic  deaf-mutes.  Accordingly  there  were  found  in  almost  all  cases 
sclerotic  and  atrophic  processes,  hut  in  addition  always  some  functionating 
parenchyma.  Hence  there  was  no  struma  whose  histological  picture  was 
characteristic  for  cretinism,  v.  Werdt  arrives  at  the  same  conclusion  on 
the  ground  of  the  examination  of  five  strumas  that  histologically  showed 
entirely  the  picture  of  a  cretin's  thyroid,  without  there  being  any  sign  of 
cretinism  whatsoever  in  the  actual  cases. 

Xo  essential  alterations  have  as  yet  been  found  in  the  parathyroid  glands 
in  cretinism  (Scholz,  Getzowa,  E.  Bircher). 

Treatment. — Before  I  consider  the  question  as  to  the  role  that  thyroid 
insufficiency  plays  in  endemic  cretinism,  I  should  like  to  speak  about  the 
results  of  thyroid  therapy.  There  are  in  the  literature  very  contradictory 
statements  as  to  this.  v.  Wagner  saw  very  good  results.  They  consisted  in 
the  disappearance  of  the  myxedematous  swellings,  in  the  rapid  development 
of  the  genitalia,  which  had  remained  behind,  in  the  diminution  in  size  of  the 
enlarged  tongue,  and  even  in  the  disappearance  of  an  umbilical  hernia,  in 
falling  out  of  the  bristly  hair  and  development  of  new  hair  of  normal  texture, 
in  acceleration  of  dentition,  before  all.  however,  in  the  diminution  in  size  of 
the  fontanelles  that  had  remained  open,  in  the  acceleration  of  ossification  and 
in  increase  in  height.  The  least  satisfactory  were  its  results  on  the  psyche; 
it  is  true  that  there  was  usually  a  decrease  in  the  apathy  and  in  the  lack  of 
movements,  yet  the  increase  in  the  intellectual  capability  was  usually  very 
slight. 

V.  Wagner  lays  especial  stress  on  the  earliest  possible  beginning  of  the 
therapy.  He  also  saw  good  results  in  individual  cases  from  administration  of 
small  doses  of  iodine  (through  stimulation  of  the  activity  of  the  thyroid 
gland?).  Still  better  results  were  obtained  by  Magnus-Levy  in  fourteen 
individuals  from  three  neighboring  villages  from  upper  Miinstertal  in  the 
Vosges.  These  individuals  came  from  seven  families.  The  cretinism  had 
appeared  in  this  neighborhood  only  a  short  time  previously;  goiters  were 
usually  present  in  the  relatives,  and  also  the  parents  showed  symptoms  of 
slight  goitrous  degeneration.  In  the  individuals  themselves  the  thyroid  was 
in  many  cases  not  palpable,  only  in  a  few  goitrously  degenerated.  The 
majority  showed  fairly  well  pronounced  myxedematous  symptoms.  In  the 
severest  cases  were  present  lordosis  and  pendulous  abdomen,  in  all  constipa- 
tion and  faulty  development  of  the  genitalia.     One  case  was  highly  deaf. 


ENDEMIC    CRETINISM  1 67 

It  is  further  worthy  of  note  that  a  case  that  had  developed  fairly  normally  up 
to  the  tenth  year  first  showed  signs  of  cretinic  degeneration  at  the  close  of  an 
attack  of  pertussis,  and  finally  in  the  sixteenth  year  showed  a  rapid  deteriora- 
tion with  distinct  signs  of  myxedema;  in  none  of  the  cases  did  there  exist  com- 
plete dementia.  In  all  these  cases  there  was  a  distinct  improvement  already, 
four  to  six  weeks  after  the  institution  of  thyroid  therapy.  After  one  and  one- 
half  years  only  one  case  showed  an  increase  in  height  as  low  as  4  cm. — all  the 
rest  11-17  cm.  The  myxedematous  manifestations  disappeared,  and  the 
intellectual  abihty  improved  considerably.  Also  v.  Eysselt  saw  good  results 
in  forty-six  cretins  in  the  Littauer  Amtbezirke  [official  district]  in  Mahren. 
In  two  the  development  of  the  genitaha  was  especially  influenced.  Also 
Sojer  saw  favorable  influencing  of  the  growth,  and  in  addition  also  a  severe 
loss  in  weight.  In  two  later  communications  v.  Wagner  reports  about  nu- 
merous cases  that  were  treated  with  very  good  results.  Also  in  these  com- 
munications V.  Wagner  points  out  that  the  results  were  more  favorable  the 
sooner  the  treatment  was  begun.  In  certain  light  cases  a  cure  may  be  ob- 
tained which  persists  even  after  withdrawal  of  the  therapy.  But  even  when 
the  therapy  is  begun  in  late  life  good  results  can  be  obtained.  In  the 
severer  grades  of  cretinism  the  result  was  indeed  not  so  satisfactory. 

Also  the  hardness-of-hearing  may  become  essentially  improved.  Many 
cases  of  hardness-of-hearing,  however,  do  not  improve. 

According  to  v.  Wagner,  cretinism  for  the  most  part  is  not  congenital,  but 
in  the  great  majority  of  cases  signs  of  cretinism  first  make  their  appearance  in 
the  first  years  of  Hfe.  For  an  early  diagnosis  are  important,  first  of  all,  the 
absence  of  disturbances  of  gait  and  speech,  then  the  pale  color  of  the  face,  the 
swelKngs  of  the  skin,  the  apathy,  the  retardation  of  the  closure  of  the  fontan- 
elles  and  the  dentition,  the  gradual  retraction  of  the  root  of  the  nose  and  the 
remaining  behind  in  growth.  In  such  cases  of  acquired  cretinism  a  much 
better  result  of  thyroid  treatment  may  be  expected. 

As  an  especially  pretty  example  of  the  increase  in  height,  I  shall  quote  the 
following  case  of  v.  Wagner:  A  fifteen-year-old  boy  is  105  cm.  tall  at  the 
beginning  of  the  treatment;  after  a  four  years'  treatment  he  has  grown  about 
43  cm.  that  is  about  29  cm.  more  than  corresponds  to  the  average  growth  at 
this  period  of  life.  The  typical  saddle-nose  and  the  apathy  have  dis- 
appeared, he  articulates  fairly  well,  the  hearing  has  improved,  etc.  On  the 
contrary,  cases  in  which  the  cretinism  appears  so  early  that  we  must  assume  a 
congenital  cretinism  are  for  the  most  part  fairly  refractory.  In  these  cases  an 
influencing  of  the  disturbances  of  speech  and  intelligence  is  completely  absent. 
But  also  in  such  cases  a  result  seems  possible  when  the  treatment  is  instituted 
a  short  time  after  birth.  Those  cases  of  v.  Wagner  which  after  an  initial  nor- 
mal development  first  remained  behind  in  body  and  mental  development  after 
an  infectious  disease  could  indeed  in  part  also  be  classified  with  sporadic 
cretinism. 


1 68  THE    CRETINIC    DEGENERATION 

On  a  still  larger  material  is  based  the  report  of  v.  Kutschera  as  to  the  treat- 
ment of  endemic  cretinism  in  the  Steiermark  at  the  cost  of  the  state.  The 
treatment  was  given  to  one  thousand  eleven  cretins;  of  these  a  great  num- 
ber was  treated  for  only  a  short  time  on  account  of  the  insuflEicient  interest 
of  the  parents  and  could  not  be  considered  in  the  judgment  of  the  result. 
Also  there  were  found  numerous  individuals  who  could  not  be  considered  as 
cretins,  and  who  were  separated  out  at  a  later  sifting.  Only  in  2.4  per  cent, 
of  all  treated  were  the  tablets  not  borne  well.  High-grade  idiots  and  cases 
of  pure  mutism  were  rejected.  Of  great  interest  were  the  cases  the  growth 
of  which  could  be  followed  for  a  long  time.  They  were  four  hundred  forty 
in  number,  of  which  only  10.2  per  cent,  showed  only  a  less  growth  than  corre- 
sponded with  the  age  of  life,  4.1  per  cent,  showed  a  growth  corresponding 
with  this  age;  85.7  per  cent.,  however,  a  growth  that  exceeded  the  normal  at 
that  age.  Especially  in  the  first  years  of  life  was  the  increase  in  height  very 
significant,  but  it  occurred,  too,  in  individuals  at  the  beginning  of  the  third 
decade,  in  whom,  under  normal  conditions,  growth  would  have  ceased.  As  to 
the  total  results,  which  also  took  into  consideration  other  cretinic  symptoms, 
among  six  hundred  seventy-seven  cases  there  was  an  appreciable  improve- 
ment in  42.8  per  cent.,  a  distinct  improvement  in  48.6  per  cent.,  and  in  8.6 
per  cent,  no  improvement  at  all. 

Again,  v.  Kutschera  reports  light,  previously  treated  cases,  in  which 
complete  cure  was  obtained  after  a  relatively  short  treatment. 

In  rather  sharp  opposition  to  these  good  results  are  the  bad  results  of 
Scholz  and  also  of  Lombroso.  The  bad  results  of  Lombroso  are  concerned  with 
old  cretins.  Scholz  reports  concerning  a  very  large  number  of  cases.  Scholz 
treated  with  thyroid  tablets  one  hundred  cretinous  children  in  the  infirmary 
at  Knittenfeld.  He  began  with  one  tablet  and  gradually  increased  to  three 
tablets,  and  in  certain  cases  up  to  eight  tablets,  per  diem.  The  results 
throughout  were  unfavorable.  The  body  weights  quickly  sank  (in  certain 
cases  as  much  as  36  per  cent.).  The  children  became  extremely  weak,  even 
bed-ridden,  the  appetite  diminished,  vomiting  and  diarrhea  occurred,  apathy 
increased;  three  children  died.  Increase  in  height  was  not  observed.  Also 
there  were  observed  other  symptoms  of  hyperthyroidism,  such  as  tachycardia, 
sweats,  etc.  v.  Wagner  believes  that  these  unfavorable  results  of  Scholz 
depend  on  too  high  dosage,  v.  Wagner  and  v.  Kutschera  gave  only  a  half- 
tablet  to  small  children  and  gradually  increased  to  one  tablet.  Also  older 
individuals  were  mostly  given  only  one  tablet  a  day.  Scholz  began  with  one 
tablet  and  increased  apparently  rather  quickly  to  three  tablets,  in  certain 
cases  even  higher.  In  my  cases  of  sporadic  cretinism,  however,  even  much 
larger  doses  were  necessary  over  even  a  longer  time  before  the  first  manifesta- 
tions of  hyperthyroidism  manifested  themselves.  Scholz  later  stated  that  he 
could  not  obtain  any  good  results  with  small  doses.  Also  v.  Wagner  stated 
that  many  severe  cases,   especially  those  which  he  regards  as  congenital 


ENDEMIC    CRETINISM  1 69 

cretinism,  are  either  fully  refractory,  or  that  at  least  certain  symptoms, 
especially  the  disturbances  of  intelligence  and  speech,  can  remain  uninfluenced. 
The  hypothesis  that  in  such  cases,  in  which  the  noxus  has  already  done  harm 
at  a  former  period,  already  definitive  irreparable  damage  has  been  done, 
especially  in  the  central  nervous  system,  can  explain  only  a  slight  result,  but 
not  the  complete  failure  of  the  thyroid-gland  treatment,  as  these  conditions 
also  obtain  in  sporadic  cretinism,  and  here  thyroid-gland  therapy  is  never 
entirely  without  [good]  results. 

We  now  take  up  the  question  as  to  what  role  the  disease  of  the  thyroid 
plays  in  endemic  cretinism. 

Pathogenesis. — Kocher  and  v.  Wagner  identify  sporadic  and  endemic 
cretinism,  referring  all  manifestations  to  a  damaging  of  the  thyroid  gland. 
Bircher,  Ewald,  and  Scholz  ascribe  to  the  arthyrosis  component  only  a  cer- 
tain signification,  and  see  in  it  only  one  manifestation  of  cretinic  degenera- 
tion which  is  coordinated  with  other  derangements. 

The  following  is  a  Hst  of  the  factors  that  speak  against  the  hypothesis 
of  a  thyroid  disturbance  alone: 

1.  The  action  of  thyroid  therapy  is  not  so  constant  as  in  sporadic  cretinism. 

2.  The  myxedematous  symptoms  are  wanting  in  many  cases  or  are  only  very 
slightly  expressed. 

3 .  The  forms  of  the  clinical  manifestations  of  endemic  cretinism  are  much 
more  manifold.  To  it  belong  the  frequent  association  with  mutism, 
further  the  occurrence  of  mutism  in  cases  that  otherwise  show  only 
few  signs  of  cretinic  degeneration.  In  endemic  cretinism  there  is  an 
incongruence  between  the  inhibition  of  the  mental  disturbances  and 
the  other  signs  of  the  cretinic  degeneration;  cases  that  on  the  one 
hand  show  struma  and  rather  high-grade  disturbance  of  growth  are, 
however,  well  developed  mentally;  on  the  other  hand,  cases  that  are 
highly  idiotic  have  remained  behind  in  growth  only  a  little. 

4.  Further,  there  exists  a  quantitative  and  qualitative  diference  in  the 
disturbance  in  growth.  This  in  endemic  cretinism  is  only  delayed; 
even  in  the  highest  grades  there  occurs  later  closure  of  the  most  of  the 
epiphysial  junctures;  the  disturbance  in  growth  is  disproportionate 
(Breus  and  Kolisko). 

5.  The  hypophysis  is  often  goitrously  degenerated. 

I  believe,  therefore,  that  I  shall  have  to  concur  in  the  opinion  of  those 
authors  who  ascribe  to  the  noxus  of  cretinic  degeneration  a  direct  deleteri- 
ous influence  on  the  central  nervous  system  and  other  tissues,  probably  also 
on  the  other  ductless  glands.  Also  the  independent  position  that  according 
to  the  later  investigations  we  must  ascribe  to  goiter  heart  is  embraced  in  the 
confines  of  this  view. 

On  the  other  hand,  the  significant  results  of  thyroid-gland  therapy  in  many 
cases  of  endemic  cretinism  force  us  to  ascribe  to  the  athyrosis  components  a  greater, 


lyo  THE    CRETIXIC    DEGEXERATIOX 

indeed  in  many  cases  an  almost  determining  significance.  The  complete 
setting  aside  of  this  factor,  as  we  see  in  the  works  of  H.  Bircher  and  Scholz, 
is  not  in  my  opinion  correct.  E.  Bircher  also  surely  goes  too  far  when  he 
explains  the  striking  influencing  of  the  inhibition  of  growth,  which  was  ob- 
served in  many  cases  of  endemic  cretinism  under  the  thyroid  medication, 
simply  through  the  evidence  that  also  the  normal  cartilages  react  to  the 
administration  of  thyroid  gland,  and  that  Scholz  and  Zingerle  favorably  in- 
fluenced the  growth  of  rachitic  dwarfs  through  thyroidin  tablets.  Such  re- 
sults, that  are  to  be  striven  after  in  all  cases,  are  not  to  be  attained  in  all. 
I  quote  examples  of  this  in  the  chapter  on  infantihsm,  in  which  the  inhibition 
of  the  osseous  growth  behaves  refractory  to  thyroid  therapy.  The  cause 
of  the  divergence  of  views  I  would  especially  see  in  the  fact  that  up  to  the 
present  we  have  too  little  considered  that  a  variable  importance  attaches  to  the 
athyrosis  components  in  diferent  individuals  and  in  diferent  epidemics.  So, 
for  instance,  in  the  epidemic  that  Magnus-Levy  described  it  stood  entirely 
in  the  foreground;  it  is  not  without  significance  in  this  respect  that  the 
epidemic  that  Magnus-Levy  described  had  lasted  only  for  a  short  time.  Also 
in  numerous  cases  of  Kocher  and  v.  Wagner  is  the  athyrosis  predominant. 
However,  v.  Wagner  states  that  the  cases  originating  in  Judenburg  did  not 
react  at  all  to  the  administration  of  thyroid.  The  same  is  true  of  the  severest 
forms  of  cretinism  in  the  Steiermark  that  Scholz  observed,  and  of  the  cases 
of  Bircher.  It  is  therefore  to  be  supposed  that  at  difterent  places  the  noxus 
works  with  dift'erent  intensity.  Significant  also  is  the  fact  as  to  whether 
the  population  has  suffered  from  the  affection  for  a  long  time;  finally  it  is 
probable  that  bad  living  conditions,  in-breeding,  and  many  other  factors 
contribute  to  the  intensity  and  the  clinical  symptoms  of  the  endemic. 

How  complicated  the  question  is,  is  shown  by  a  communication  of  v. 
Wagner^s  as  to  marine  cretinism.  It  is  known  that  the  seacoasts  are  almost 
free  from  goiter  and  cretinism.  Now  v.  Wagner  observed  on  the  island 
Veglia,  belonging  to  the  Guarneric  Islands,  fifteen  dwarfs,  mostly  about 
loo  cm.  tall.  The  closure  of  the  fontanelles  was  delayed;  in  most,  but  not 
in  all,  the  root  of  the  nose  was  retracted,  there  existed  more  or  less  distinctly 
well-expressed  myxedema  of  the  skin,  high  voice;  there  was  absence  of  hair  on 
the  pubic  and  in  the  axillary  regions;  the  genitals  showed  high-grade  infantil- 
ism, in  men  the  mons  Veneris  was  abundant  in  fat  and,  as  is  shown  in  the 
photographs  accompanying  v.  Wagners's  publication,  was  limited  above  by  a 
horizontalline;  frequently  there  existed  constipation,  dentition  was  delayed, 
the  intelligence  in  some  was  only  very  slight,  in  others  there  existed  only 
slight  apathy;  many  could  not  read  and  write;  the  hearing  was  well  developed 
in  all.  The  thyroid  gland  was  not  palpable  in  all  of  them.  v.  Wagner 
discusses  the  question  whether  these  cases  are  to  be  classified  under  endemic 
cretinism.  As  ground  against  such  classification,  v.  Wagner  adduces:  the 
complete  freedom  from  goiter  of  the  neighborhood,  the  marked  dwarfism  of 


ENDEMIC    CRETINISM  171 

all  individuals,  the  marked  dysgenitalism,  the  normal  development  of  hearing 
and  the  relatively  good  development  of  speech,  v.  Wagner  believes  that 
the  in-breeding  that  exists  on  this  island — also  albinism  is  indigenous  here — 
perhaps  plays  a  "role  in  this,  but  that  also  the  insufficiency  of  the  thyroid 
gland  is  the  decisive  factor.  Very  striking  seems  to  me  the  circumstance 
that  in  all  individuals  at  first  the  development  was  entirely  normal  up  to  the 
third,  the  fifth,  indeed  even  the  tenth  year  and  the  inhibition  of  growth  did 
not  set  in  until  this  age;  the  accompanying  photograph  shows,  in  addition  to 
the  marked  dysgenitalism,  a  form  of  obesity  such  as  we  are  wont  to  find  in 
dystrophia  adiposo-genitalis  and  to  refer  to  the  insufficiency  of  the  inter- 
stitial glands  or  of  the  hypophysis.  The  disturbance  of  growth  seems  to 
me  to  speak  decisively  for  the  hypophysis.  A  strumous  degeneration  of  the 
hypophysis  could  perhaps  have  been  demonstrated  by  an  enlargement  of  the 
sella  on  X-ray  examination;  in  other  cases  there  did  exist,  however,  un- 
doubted myxedematous  alterations.  Such  an  endemic  degeneration  of  the 
ductless  glandular  system  with  predominant  involvement  of  the  glandular  hy- 
pophysis occurring  in  earliest  youth  is,  at  all  events  up  to  the  present,  unique. 
I  cannot  at  first  hand  answer  with  certainty  the  question  as  to  whether  or 
not  a  variety  of  cretinic  degeneration  exists  in  such  a  case. 

Surveying  once  more  the  field  covered  in  the  preceding  observations  it 
seems  to  me  that  the  separation  of  the  cretinic  degeneration  from  the  chapter 
of  the  pathology  of  the  thyroid  gland  is  indeed  possible  and  desirable,  on  the  other 
hand  it  would  be  a  mistake  to  relegate  too  far  to  the  background  the  intimate 
connecting  associations  with  the  thyroid  gland.  The  separate  position  depends 
on  the  localization  to  certain  territories,  depending  on  the  fact  that  the  noxus 
contained  in  the  thyroid  gland  produces  very  frequently,  perhaps  even 
regularly,  alterations  not  only  in  the  thyroid  gland  but  also  in  numerous 
organs  such  as  the  heart  and  the  central  nervous  system. 

But  there  are  other  attempts  at  explanation  that  I  have  not  as  yet  men- 
tioned. V.  Kutschera  supposes  an  infectious  noxus;  he  bases  the  assumption 
on  the  following  observation:  dogs  that  have  been  brought  up  in  the  bed  of  a 
cretin  remained  behind  in  development  and  became  typically  cretinic.  Of 
course  it  must  be  considered  that  these  dogs  were  under  the  same  external 
conditions  as  human  beings  and  drank  the  same  water.  Very  difficult  to 
interpret  is  also  the  observation  of  v.  Wagner  that  a  dog  with  typical  endemic 
cretinism  shows  extensive  retrogression  of  the  cretinic  symptoms  after  extirpa- 
tion of  the  goiter,  v.  Wagner  assumes  that  the  manifold  symptoms  of  en- 
demic cretinism  are  produced  by  a  poison  emanating  from  the  goiter,  and 
therefore,  as  previously  mentioned,  places  the  thyroid  gland  as  the  central 
figure  in  the  pathogenesis. 

Differential  Diagnosis. — The  differentiation  between  sporadic  and  en- 
demic cretinism  is  often  difficult  and  in  certain  cases  may  be  impossible.  The 
fact  that  the  cretin  comes  from  a  locality  in  which  cretinism  is  endemic 


172  THE    CRETIXIC    DEGENERATION 

naturally  is  not  evidence,  as  sporadic  cretinism  may  also  occur  in  some 
infested  neighborhood.  The  coming  from  a  neighborhood  where  only  goiter 
but  not  cretinism  is  endemic  cannot,  without  other  factors,  be  used  against 
the  diagnosis  of  endemic  cretinism,  as  in  such  neighborhoods  endemic  cre- 
tinism may  occur.  I  refer  once  more  to  the  small  endemic  described  by 
Magnus-Levy.  Here  too,  seems  to  me,  belongs  the  interesting  observation 
of  Eller.  Eller  describes  three  cases  of  cretinism  in  a  Vienna  family.  The 
patients  were  goitrous  and  had  never  been  out  of  Vienna;  three  sisters  were 
entirely  well;  the  cretins  themselves  had  strumas.  The  result  of  the  treat- 
ment with  thyroid,  which  was  not  carried  out  perseveringly,  was  not 
satisfactory. 

The  finding  of  a  struma,  slight  or  absent  myxedematous  consistency  of 
the  skin,  incongruity  between  mental  development  and  the  rest  of  the  symp- 
toms, relatively  slight  inhibition  of  ossification  and  closure  of  the  fontanelles, 
unequal  remaining  behind  of  the  epiphysial  closures,  slight  or  absent 
results  of  treatment,  impossibility  of  stimulating  the  metabolism  with 
thyroidin,  low  tolerance  for  thyroid-gland  substance  speak  for  endemic 
cretinism.  As  far  as  the  disturbance  in  ossification  is  concerned,  it  must  be 
considered  that  this  occurs  in  many  vegetative  disturbances  that  have  noth- 
ing to  do  either  with  the  thyroid  gland  or  with  endemic  cretinism,  v.  Wyss 
already  pointed  this  out;  he  found  in  four  of  seven  individuals  who,  without 
showing  striking  symptoms  of  cretinism  had  remained  behind  physically  and 
mentally,  pronounced  inhibition  of  growth  and  of  ossification,  which  were  in 
no  wise  different  from  those  which  are  typical  for  endemic  cretinism.  We 
must  therefore  agree  with  v.  Wyss  that  in  a  country  in  which  cretinism  is 
endemic  the  differentiation  between  cretins  and  idiots  is  extraordinarily 
diflicult.  The  delay  in  ossification  seems  to  be  found  regularly  in  cretinoids 
without  mental  defect. 

Addendum 

Goiter  is  not  at  all  uncommon  in  the  United  States.  A  close  study 
would  perhaps  show  that  goiter  is  confined  in  this  country  to  certain  districts. 
Clark  and  Pierce  mention  that  there  are  certain  districts  of  endemic  goiter  in 
the  region  of  the  Great  Lakes  and  certain  sections  of  West  Virginia. 

McCarrison  was  able  to  produce  swelling  of  the  thyroid  experimentally 
in  men  by  administering  to  them  the  filtrate  of  boiled  water  from  a  goitrous 
district.  This  author  cites  facts  that  make  it  very  probable  that  the  noxus  of 
goiter  exists  in  the  soil,  and  may  possibly  be  transmissible  from  individuals. 

Blood  counts  from  seventy-three  cases  of  goiter  made  under  the  direction 
of  McCarrison  showed  a  lessening  of  the  polymorphonuclear  leucocytes  in 
98.9  per  cent,  of  the  cases  and  increase  of  the  small  mononuclear  leucocytes 
in  92.5  per  cent.,  an  increase  of  the  eosinophiles  in  88  per  cent.,  and  an  in- 
crease of  the  large  mononuclear  cells  in  only  23  per  cent,  of  cases.     The 


ADDENDUM  I 73 

author  regards  as  misleading  and  valueless  Kocher^s  blood  count  as  a  cri- 
terion of  differentiation  between  exophthalmic  and  nonexophthalmic  goiter. 
He  treats  goiter,  with  striking  reduction  of  the  goiter,  by  the  use  of  intes- 
tinal antiseptics  such  as  salol  and  thymol,  milk  soured  by  the  bacillus  bul- 
garicus  and  the  injection  of  vaccines  prepared  from  bacillus  coli.  His 
publication  contains  a  map  showing  how  goiter  is  distributed. 

Gilbride  has  made  a  bacteriological  examination  of  the  contents  of  eight 
cystic  goiters,  with  negative  results,  save  in  one  case  in  which  he  found  the 
streptococcus  vermiformis  of  Sternberg.  McCarrison  states  that  Horand  has 
reported  the  presence  of  a  parasite  in  a  goitrous  cyst,  but  adds  that  in 
neither  this  work  nor  in  that  of  Gilbride  is  there  sufficient  evidence  to  justify 
the  suspicion  that  the  organisms  found  are  causal  agents  in  the  production  of 
goiter. 

References 

Clark  (r.),  and  Pierce  (C.  C).  Endemic  goiter.  Its  possible  relationship  to  water 
supply.     U.  S.  Public  Health  Reports,  April  17,  1914. 

McCarrison  (R.).  The  etiology  of  endemic  goiter.  London,  John  Bale  Sons  & 
Danielsson,  19 13. 

Gilbride  (J.  J.).  Cultures  from  the  thyroid  gland  in  goiter.  A  bacteriologic  study 
of  fourteen  cases.     J.  Am.  M.  Ass.,  Chicago,  191 1,  LVII,  p.  1988. 

Horand  (R.).  Examen  a  I'ultramicroscope  du  liquide  du  goitre  kystique;  presence 
d'un  parasite.     Rev.  gen.  de  Clin,  et  de  Therap.  Par.,  1911,  XXV,  p.  71. 


CHAPTER  IV 

THE  DISEASES  OF  THE  PARATHYROID  GLANDS 
(Glandulae  Parathyreoidae) 

[Parathyroid  Glandules,  Epithelial  Bodies,  Epithelkorperchen] 

Anatomy. — The  parathyroid  glands  are  paired  organs  showing  intimate 
spatial  relationship  with  the  thyroid  gland.  In  man  there  are  usually 
two  parathyroid  glands  on  each  side.  They  have  a  length  diameter  of 
3-15  mm.  and  a  thickness  or  width  of  about  2  mm.  According  to  Erd- 
heim,  the  upper  parathyroid  glands  (epithelial  bodies)  lie  against  the  posterior 


Gl.  plh. 


Gl.  plh. 


Fig.   23. — Parathyroid  bodies  of  man  (according  to  Zuckcrkandl).     Posterior  view  of  organs  of 
neck.     Gl.  plh.  =  parathyroid  glands. 

surfaces  of  the  lateral  lobes  of  the  thyroid  gland  about  the  middle  of  the 
height  of  the  lobes,  and  the  lower  parathyroids  lie  toward  the  lower  pole 
of  these  lobes;  but  not  rarely  there  are  exceptions  with  regard  to  both  number 
and  position  of  the  parathyroids.  On  one  side  there  may  be  as  many  as 
three  or  four  of  these  bodies  (Schrieber  et  al.) ;  the  lower  bodies  may  lie  as 

174 


ANATOMY   AND    EMBRYOLOGY  1 75 

low  as  against  the  upper  pole  of  the  thymus.  Statements  even  exist  that 
accessory  parathyroids  are  pushed  down  to  the  pericardial  fatty  tissue 
{Vassale  and  Piano).  The  bodies,  especially  the  upper,  are  bound  to  the 
thyroid  gland  by  connective  tissue,  and  the  upper  may  also  in  part  be  inter- 
polated in  the  thyroid  tissue.  We  find  in  the  different  species  of  animals 
great  variations  in  the  number  and  position  of  the  parathyroids.  In  the 
cat,  the  upper  parathyroid  is  always  imbedded  in  the  thyroid  tissue ;  in  the 
dog  it  is  sometimes  fully  imbedded  there  (inner  parathyroid,  KoJin),  so  that 
extirpation  of  the  parathyroids  alone  may  be  attended  with  great  difficulty. 


Fig.  24. — Parathyroid  gland.     F.  C.  =  fat  cells;  eos.  C.  =  eosinophilic  cells;  C.  C.  =  chief  cells. 

It  is  especially  important,  moreover,  that  in  herbivorous  animals  the  para- 
thyroids are  entirely  apart,  spatially  from  the  thyroid  gland. 

The  parathyroids  are  very  abundantly  supplied  with  blood.  Between 
the  individual  cell  groups  are  found  numerous  strikingly  wide  capillaries. 
The  glands  are  supplied  by  the  inferior  thyroid  artery. 

Histologically  the  parathyroids  are  characterized  b}'  great  richness  in 
cells.  According  to  Welsh,  large  polygonal  chief  cells  and  smaller  so-called 
oxyphilic  cells  are  to  be  distinguished  from  each  other. 

Embryology. — The  parathyroids  are  entodermal  glands  (Verdun).  Fig.  3 
shows  how  the  parathyroids  and  the  thymus  gland  originate  from  the 
branchial  arches. 

The  epithelial  bodies  (e^  and  ei)  come  from  the  dorsal  part  of  the  third 


176  THE   DISEASES    OF    THE    PARATHYROID    GLANDS 

and  fourth  branchial  pouch.  The  thymus  gland  comes  from  the  ventral  part 
of  the  third  pouch. 

If  the  bilaterally  arranged  thymus  gland  becomes  pushed  down  the  para- 
thyroids may  come  to  rest  on  the  thymus  gland  or  even  to  be  included  in  its 
substance.  From  the  illustration  it  will  be  also  seen  that  the  relationship 
of  the  parathyroids  to  the  thyroid  is  purely  topographical.  £4  represents 
the  inner  parathyroid  gland  which  may  eventually  become  included  in  the 
tissue  of  the  thyroid. 

Historical. — It  will  be  seen  from  the  intimate  spatial  relationship  between 
the  thyroid  and  the  parathyroids  why  for  a  long  time  the  functional  inde- 
pendence of  the  parathyroids  was  not  recognized.  As  a  sequence  of  the 
first  attempts  at  total  thyroidectomy,  by  Schif,  Kocher,  Rivardin,  v.  Eisel- 
herg  and  others,  there  were  observed,  in  addition  to  the  results  of  the  absence 
of  the  thyroid  as  described  in  Chapter  II,  severe  acute  manifestations  that 
were  uncommonly  like  the  tetany  that  had  formerly  been  observed  in 
human  pathology.  The  difference  in  topography  of  the  parathyroids  in 
different  animal  species,  as  just  described,  makes  intelligible  why  in  some 
species  thyroid  extirpation  led  to  cachexia  strumipriva,  in  others  to  tetany. 
The  discovery  of  the  parathyroids,  in  1880,  by  Sandstrom,  first  made  a 
change  in  this  respect.  Indeed  Sandstrom  at  first  regarded  the  bodies  described 
by  him  as  the  embryonal  stages  of  thyroid  tissue  that  had  remained  at  a 
standstill;  Gley,  who  in  189 1  first  discussed  the  physiological  significance  of 
the  parathyroids,  believed  that  these  bodies  would  assume  the  function 
of  the  thyroid  on  extirpation  of  that  gland.  A.  Kohn  first  taught  the 
anatomical  independence  of  the  parathyroids;  Moussu,  and  Vassale  and 
Generale  their  functional  independence.  Kohn  also  introduced  the  term 
*'Epithelkorperchen."  The  investigations  of  Pineles,  Biedl,  Erdheim  and 
others  to-day  place  the  independence  of  the  parathyroids  beyond  question. 
The  observations  of  aplasia  of  the  thyroid  with  retention  of  the  parathyroids, 
as  detailed  in  chapter  on  the  thyroid,  showing  the  complete  picture  of 
deficiency  of  the  thyroid  with  no  symptoms  whatever  of  tetany,  further 
the  fact  that  the  absence  or  deficiency  of  thyroid  gland  only,  not  however 
that  of  the  parathyroids,  is  made  good  by  thyroidin  therapy,  and  finally  the 
fact  established  in  animal  experimentation  that  extirpation  of  the  para- 
thyroids alone  leads  to  tetany  but  not  to  myxedema,  7nake  certain  the 
teaching  of  the  physiological  independence  of  the  parathyroids  and  have  furnished 
the  demonstration  that  tetany  has  nothing  to  do  -with  the  absence  of  thyroid 
gland,  but  depends  on  an  insufficiency  of  the  function  of  the  parathyroids. 

It  is  only  one  step  from  this  knowledge  to  the  view  that  the  different  forms 
of  tetany  observed  in  human  pathology  (parathyroprivic  tetany) ,  idiopathic 
or  occupation  tetany,  tetany  of  children,  tetany  of  maternity,  stomach 
tetany,  tetany  in  infectious  diseases  and  poisonings,  etc.,  depend  on  a 
uniform  pathological  basis,  and  that  at  the  bottom  of  all  is  an  absolute  or 


TETANY  177 

relative   insufficiency   of   the  parathyroids    {Jeandelize,  Pineles,   Escherich, 
Erdheim,  Chvostek,  Jr.,  Rudinger,  and  others). 

a.  Aparathyrosis  or  Hypoparathyrosis,  Tetany 

Definition. — By  tetany  we  mean  an  abnormally  increased  condition  of 
excitement  of  the  nervous  system,  which  is  demonstrable  in  a  heightened  excitability 
of  the  motor,  sensible,  sensory  and  vegetative  nerves,  and  under  certain  circum- 
stances, in  paresthesias,  and  bilateral  intermittent,  for  the  most  part  painful, 
spasms,  with  intact  consciousness,  or  which  becomes  manifest  through  phenomena 
of  irritation  on  the  part  of  the  vegetative  nerves.  To  the  picture  of  tetany  belong 
also  trophic  and  certain  metabolic  disturbances.  The  manifestations  are  the 
result  of  an  insufficiency  of  the  parathyroid  glands. 

Symptomatology. — Increase  in  the  electric  excitability  is  to  be  regarded, 
next  to  spasms,  as  the  most  important  cardinal  symptom  of  tetany.  It 
affects  in  the  first  place  the  peripheral  motor  nerves  (Erb),  although  the  sen- 
sory senses  (Hoffman),  and  the  nerves  of  special  sense  (acusticus-C/rc^o^te^, 
Jr.),  are  overexcitable  to  electricity.  This  h}^erexcitability  is  found  espe- 
cially on  the  use  of  the  galvanic  current;  the  faradic  excitability  is  most  often 
normal.  The  ulnar  nerve  serves  best  for  testing  in  adults;  the  peroneal 
nerve  in  children.  We  should  use  Stintzing's  normal  electrode  (3  sq.  cm.) 
and  Edelmanns  horizontal  galvanometer.  The  hyperexcitability  expresses 
itself  not  only  in  a  lessening  of  the  irritation  threshold  against  the  cathodal 
closing  contraction,  but  also  in  a  definite  alteration  of  the  contraction  formula. 
In  normal  individuals  the  lower  limits  for  the  C.C.C.  lies  at  about  0.9  milli- 
ampere  for  the  ulnar  nerves,  for  the  A.C.C.  at  about  1.5  to  2  milliamperes, 
for  the  A.O.C.  about  2.5-3  rnilliamperes,  for  the  C.C.Te  about  5  milli- 
amperes. and  the  C.O.C.  can  hardly  be  obtained  even  with  high  amperage. 
Now  in  tetany  the  C.C.C.  can  fall  to  very  low  values  (as  low  as  o.i  milli- 
ampere,  and  also  the  values  for  A.C.C.  fall  (even  to  0.5  milliampere) ;  it  is 
important,  however,  that  the  value  for  the  A.O.C.  fall  and  eventually  be- 
come lower  than  that  of  A.C.C.  and  even  lower  than  that  of  C.C.C.  Further 
C.C.Te  occurs  at  very  low  values,  and  finally  also  C.O.C.  may  be  ob- 
tained. Also  A.C.Te  and  A.O.Te  may  be  obtained  sooner.  The  first 
statements  as  to  the  galvanic  hyperexcitability  came  from  Kussmaul  and 
Benedict;  the  first  exact  measurements  were  made  by  Erb.  In  the  tetany 
of  children,  first  Escherich  and  Jauregg  v.  Wagner  pointed  out  the  galvanic 
hyperexcitability.  Thiemich  regarded  the  falling  of  C.O.C.  below  5  milli- 
amperes as  conclusive  for  the  diagnosis.  It  was  shown,  however,  by  v. 
Pirquet  that  this  relation  obtains  only  in  the  most  severe  cases  and  that  the 
slight  grades  of  tetany  are  first  recognized  in  a  falling  of  the  value  for  A.O.C, 
in  the  so-called  anodal  hyperexcitability. 

Erb's  phenomenon  may  be  present  in  the  most  of  the  motor  nerves  ac- 


178  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

cessible  for  the  test.  For  the  most  part  it  is  present  in  like  intensity  in 
symmetrical  nerves,  although  there  are  exceptions  to  this  rule.  For  in- 
stance V.  Frankl-HocJiwart  found  in  the  right  ulnar  in  a  case  a  C.C.C.  of  0.3 
milliampere,  in  the  left  ulnar  a  C.C.C.  of  o.i  milliampere.  ErVs  phenom- 
enon, like  all  the  symptoms  of  tetany,  shows  great  variations.  It  is  most 
distinct  at  the  onset  or  during  the  acute  exacerbations,  less  distinct,  as  a 
rule,  during  the  intervals.  In  the  chronic  tetany  that  extends  through  many 
years  the  galvanic  excitability  can,  during  the  interval  free  from  attacks,  ap- 
proach the  lower  limiting  values  of  the  normal,  and  may  even  show  values 
as  high  as  for  normal  individuals.  As  v.  Frankl-Hochii'art  points  out,  this 
relation  is  beautifully  shown  in  the  tetany  of  maternity;  here  the  galvanic 
hyperexcitability  is  seen  only  during  pregnancy  or  lactation.  Erh's  phe- 
nomenon is  the  most  important  symptom  of  tetany,  because  w^e  as  yet  know 
of  no  other  condition  in  which  it  occurs.  It  is  also  very  frequent,  v.  Frankl- 
Hochwart  says  that  he  has  not  seen  any  acute  case  of  tetany  with  normal 
electrical  excitability;  exceptions  do,  however,  extremely  rarely,  occur. 
Kahn  and  /  observed  a  case  of  chronic  tetany  with  acute  exacerbations,  in 
which  all  the  important  symptoms  of  tetany  were  present  pronouncedly,  but 
ErVs  phenomenon,  in  spite  of  the  presence  of  severe  spasms,  was  absent 
during  the  first  days.  The  condition  amehorated;  ErVs  phenomenon  was 
positive  only  on  an  acute  exacerbation  of  the  illness,  which  occurred  after 
about  two  weeks. 

A  heightened  excitability  to  the  electric  current  is  shown  by  the  sensory 
nerves  also  (Hojfmann).  We  usually  test  the  ulnar  nerve.  Paresthesias 
occur  in  its  distribution  even  on  very  low  values  of  the  C.C.C.  There  occurs 
too  an  analogous  change  in  the  sensation  formula.  Finally  the  nerves  of 
special  sense  may  be  hyper  excitable.  With  relatively  low  current  strengths, 
Chvostek,  Jr.,  found  sensory  reactions  in  the  acoustic  nerve  with  analogous 
alterations  in  the  formula  of  sensation  in  six  out  of  seven  cases  of  tetany,  v. 
Frankl-Hochwart  found  a  similar  relation  to  the  galvanic  current  of  the 
taste  sensations.  Occasionally,  in  testing  the  electrical  excitability,  when 
the  electrode  is  placed  over  the  mastoid  process  there  occur  with  very  low 
current  strength,  and  often  before  the  occurrence  of  contraction,  ear  noises 
and  finally  a  bitter  taste  sensation  [Falta  and  Kahn).  These  symptoms  are 
subject  to  great  variation. 

Another  certain  symptom  of  latent  as  well  as  manifest  tetany  is  the 
mechanical  hyperexcitability  of  the  motor  and  sensory  nerves.  Chvostek,  Sr., 
first  pointed  out  in  this  regard,  that  in  tetany  percussion  of  the  motor  nerve 
trunks  and  especially  the  facial  trunk  leads  to  lightning-like  contractions  in 
the  muscles  supplied.  When  the  facial  trunk  is  struck,  the  contractions 
rarely  affect  the  muscles  of  the  forehead,  v.  Frankl-Hochivart  distinguishes 
three  degrees  of  the  phenomenon  depending  on  the  intensity.  In  Chvostek 
I  on  percussion  of  the  vicinity  of  the  auditory  meatus  contractions  occur  in 


TETANY  179 

the  muscles  that  close  the  eyelids,  in  those  of  the  alae  nasi,  and  in  those  of 
the  corner  of  the  mouth.  They  may  even  be  brought  about  by  sHght 
stroking  of  the  front  of  the  ear  with  the  handle  of  the  percussion  hammer 
(Sclncltze).  In  Chvostek  II  there  are  contractions  of  the  ate  nasi  and 
muscles  of  the  corner  of  the  mouth  on  percussion  under  the  zygomatic 
arch.  In  Chvostek  III  percussion  here  causes  contractions  of  the  corner  of 
the  mouth  only.  As  to  the  pathognomonic  significance  of  the  different 
degrees  of  Chvostek' s  phenomena  for  tetany  opinions  are  at  variance. 

The  phenomenon  is  certainly  very  frequent  in  tetany,  yet  it  may  be 
wanting  in  pronounced  cases  and  often  show^s  great  variations.  On  the 
other  hand  slight  degrees  of  it  may  occur  in  numerous  cases  of  neurasthenia, 
hysteria,  and  epilepsy,  v.  Frankl-Hochn'art  and  Schlesinger  found  Chvostek 
II  and  ///  in  nearly  one-half  of  patients  with  phthisis.  However,  other 
authors,  for  example  Schonhorn  (Heidelberg),  do  not  find  this  phenomenon 
so  frequent.  It  is  found  commonly  also  in  rachitis.  Kahn  and  /  found 
it  several  times  in  rachitis  tarda.  Mager  found  it  very  frequently  in 
enteroptosis,  v.  Frankl-Hochwart  in  strumous  individuals.  It  is  especially 
frequent  in  all  possible  sorts  of  cachexia,  especially  when  this  is  associated 
with  much  loss  of  water  from  the  body.  Curschmann  especially  has  pointed 
this  out.  Kahn  and  /  observed  it  also  in  severe  diabetes,  and  also  in  almost 
all  cases  of  Reichmann's  disease.  It  is  probable  that  in  a  great  number  of 
such  cases  this  phenomenon  depends  not  so  much  on  the  mechanical  ex- 
citability of  the  nerves  as  on  that  of  the  levator  anguh  oris  muscle,  as  we 
tap  too  on  the  insertion  of  this  muscle  in  the-  procedure.  For  this  view 
speaks  the  fact  that  in  the  conditions  named  idiomuscular  prominences  were 
produced  regularly  on  the  various  muscles. 

Chvostek  II  and  ///  are  also  seen  not  rarely  in  entirely  normal  individuals. 
Hence  they  are  not  pathognomonic  for  tetany,  although  it  should  be  noted 
that  these  phenomena  are  very  frequent  in  the  localities  in  which  tetany  is 
endemic  at  the  season  of  the  tetany,  and  that  in  cases  of  tuberculosis  in 
which  they  were  present  they  were  not  infrequently  found  associated  with 
caseation  of  certain  of  the  parathyroids.  Chvostek  I,  when  pronounced, 
speaks  very  loudly  for  tetany;  although  absence  of  the  symptom  does  not 
speak  against  tetany,  as  it  may  be  wanting  in  the  acute  stages,  and  like  all 
symptoms  of  tetany,  shows  great  variations.  The  mechanical  h}-perex- 
citability  of  the  sensory  nerves  expresses  itself  in  the  occurrence  of  a  burn- 
ing sensation  on  percussion  of  the  nerve  trunk  or  on  pressure  over  the  same. 
I  shall  speak  later  about  the  mechanical  excitability  of  the  sympathetic 
nerves  of  the  blood-vessels. 

Trousseau's  phenomenon  consists  in  the  circumstance  that  pressure 
on  a  nerve  trunk  will  bring  about  a  typical  tetanic  spasm  in  the  area  of  dis- 
tribution of  the  same,  or  that  the  constriction  of  an  extremity  ^^'ith  a  rubber 
bandage  will  also  induce  such  a  spasm.     This     phenomenon  has  nothing 


l8o  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

to  do  with  alterations  in  the  circulation,  but  depends  on  the  excitability 
of  the  nerve  itself  {v.  Frankl-Hochwart) .  However,  it  cannot  be  so  simply 
explained  by  the  increased  motor  irritability  of  the  nerve  alone,  for  v.  Frankl- 
Hochwart  saw  bilateral  spasms  occur  after  pressure  on  the  nerve  plexus  of 
one  extremity,  and  SchJesingcr  shows  that  this  phenomenon  cannot  be  in- 
duced on  the  purely  motor  facial  nerve,  but  only  on  the  mixed  nerves.  Hence 
to  the  hyperexcitability  of  the  motor  nerves  must  be  superadded  that  of 
the  sensory  nerves  or  of  their  spinal  centers  and  their  connecting  links 
[Schaltstiicke]. 

In  similar  manner  would  be  explained  the  leg- phenomenon  lately  de- 
scribed by  Schlesinger.  On  flexion  at  the  hip- joint  of  the  leg  that  is  ex- 
tended at  the  knee  there  can  be  induced  under  circumstances  during  the  time 
of  the  freedom  from  attacks,  a  painful  tonic  spasm  in  the  extremity,  after 
from  a  few  seconds  to  three  minutes.  Finally  should  be  mentioned  here 
the  thermic  hyperexcitability  described  by  Kashida.  This  expresses  itself 
in  the  occurrence  of  paresthesias  and  spasms  on  the  application  of  cold  or 
hot  irritants. 

In  tetany  the  tendon  reflexes  are  mostly  normal,  in  the  attack  not  rarely 
diminished. 

Finally  it  should  be  mentioned  that  the  patient  frequently  complains 
of  pains  in  the  hones  or  joints  {Falta  and  Kahn),  especially  after  severe  tetanic 
attacks.     I  shall  later  report  such  a  case. 

We  now  come  to  a  symptom  that  in  the  full  development  of  tetany  makes 
it  one  of  the  most  dreadful  diseases,  and  that  has  furnished  its  name,  i.e.,  the 
tetanic  spasm.  Here  we  meet  with  the  greatest  difTerences  in  the  phenomena, 
and  here  the  individual  forms  of  tetany  show  the  greatest  variations  in  the 
localization  of  the  spasm.  In  tetany  of  adults  usually  the  upper  extremities 
are  involved  symmetrically  in  the  spasm,  and  indeed  in  the  known  obstetri- 
cian's position,  yet  there  sometimes  occur  fist-positions  with  extended 
thumbs,  and  spasms  may  occur  unilaterally  {v.  Frankl-Hochwart,  v.  Jaksch, 
Curschmaiin,  et  al.).  When  the  lower  extremities  are  affected,  they  are 
extended,  the  foot  is  in  a  slight  cquinovarus  position,  the  toes  are  bent  plan- 
tarly,  sometimes,  however,  dorsally.     The  spasms  are  exquisitely  painful. 

As  example  I  cite  the  following  case  (Case  \T  of  Falta  and  Kahn). 

Observation  XVII. — Augustine  Sch.,  four  and  one-half  years  old,  from  Menna. 
Entered  the  clinic  Nov.  24,  191 1.  For  three  weeks  emaciation,  and  very  poor  appetite. 
One  of  the  two  children  of  the  same  parents  died  in  1909,  in  the  first  year  of  life,  of  spasm 
of  the  glottis.  The  patient  herself  had  had  spasms  at  two  and  one-half  years,  that  lasted 
two  days  and  were  associated  with  fever.  No  rickets.  Aug.,  1910  to  Jan.,  191 1  pertussis, 
then  pneumonia  with  measles.  Since  that  time  frequent  severe  diarrheas  for  eight  days; 
on  Feb.  22  vomiting  daily,  since  which  six  to  seven  bowel  movements  daily.  Since  this 
morning  tonic  spasms  in  the  feet. 

The  illustration  shows  the  typical  obstetrician's  position  of  the  hands.  .\lso  there 
is  distinct  spasm  of  the  left  leg,  as  is  to  be  seen  by  the  tension  of  the  tendon  of  the  tibialis 


TETANY 


I8l 


anticus  muscle  and  by  the  dorsal  flexion  of  the  great  toe.     The  diarrheas  ceased  on  Feb. 
15  (administration  of  tanningen),  and  the  tetanic  attacks  disappeared. 

In  children  there  occurs  the  so-called  carpopedal  spasms  in  which  the 
fingers  do  not,  as  in  the  previous  case,  assume  the  obstetrician's  position, 
but  are  spread  out.  In  involvement  of  the  face,  this  expresses  itself  in  a 
tension  of  the  muscles,  in  spasm  of  the  lids,  in  slight  pointing  of  the  mouth 
(fish-mouth  position,  "tetany  face"  of  Ufenheimer),  in  spasms  of  the  masse- 
ter,  of  the  geniohyoglossus,  and  hyoglossus  muscles  (yawning  spasms),  in 
difficulty  of  speech  on  account  of  the  tonic  rigidity  of  the  tongue,  and  eventu- 
ally in  convergence  or  strabismus  with  the  occurrence  of  double  vision. 
Sometimes  the  trunkal,  nuchal,  and  abdominal 
musculature  is  involved.  Finally  the  diaphrag- 
matic and  the  intercostal  muscles  may  be 
affected,  producing  dyspnea.  Bechterew  could 
produce  spasm  of  the  diaphragm  directly  by 
pressure  over  the  phrenic  nerve.  As  is  known, 
the  involvement  of  the  muscles  of  the  larynx  is 
very  common  in  children.  Here  the  laryngo- 
spasm  often  stands  well  in  the  foreground. 
Moreover,  the  rest  of  the  respiratory  muscles 
are  mostly  involved.  There  occurs  inspiratory 
retraction,  and  even  lightning-like  closure  of  the 
glottis  (tetanus  aponicus) ;  more  rarely  expira- 
tory apnea  also  (Escherich).  Also  in  adults 
laryngospasms  occur  not  at  all  rarely,  as 
Pineles  points  out  especially.  Finally  we  must 
mention  the  rare  retching  spasms.  In  the 
tetany  of  animals  in  which  the  parathyroids 
have  been  removed,  these  occur  not  at  all 
rarely;  here  it  is  associated  with  vomiting.  The 
transversely  striated  sphincters  of  the  bladder 
and  rectum  for  the  most-  part  remain  free,  al- 
though difficulty  in  urinating  is  sometimes  seen 
{v.  Frankl-Hochwart) . 

The  duration  of  the  spasms  is  often  very 
short,  although  at  times  it  is  hours  long.  The 
patients  often  sit  for  a  long  time  with  retracted  abdomen,  the  extrem- 
ities in  the  position  described,  incapable  of  movement.  Sometimes  there 
occurs  only  a  single  spasmodic  attack;  in  other  cases  the  attacks  are 
repeated  at  longer  or  shorter  intervals;  in  children  are  observed  as  many 
as  eighty  laryngospastic  attacks  a  day. 

The  most  manifold  factors  may  bring  about  the  spasm.     In  acute  cases 
a  slight  excitation,  percussion  of  the  abdominal  musculature,  may  lead  to  a 


Fig.     25. — Obstetrician's    posi- 
tion of  the  hands  in  tetany. 


102  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

spasm.  In  latent  tetany  a  febrile  affection  (angina,  tuberculin  injection, 
gastrointestinal  indisposition,  introduction  of  the  stomach  sound,  pregnancy, 
an  intoxication,  etc.)  may  render  the  tetany  manifest. 

Chvostek,  Jr.,  observed  the  occurrence  of  spasms  after  injection  of  tuber- 
culin. Rudinger  and  /  regularly  saw  spasms  in  the  acute  stages  occur  after 
injection  of  adrenalin.  Kahn  and  /  saw  in  the  acute  stage,  also  regularly,  the 
occurrence  of  increase  in  intensity  of  the  tetanic  symptoms  during  the  hours 
following  the  injection  (as  will  be  considered  later). 

Fibrillary  contraction  of  the  muscles,  which  are  constant  in  the  tetany 
of  parathyroidectomized  animals,  occur  in  human  tetany  rarely.  The  same 
is  also  true  as  regards  the  pareses,  which  occur  very  frequently  in  totally 
parathyroidectomized  animals,  especially  in  the  hind  extremities. 

Weakness  of  the  extremities,  especially  after  the  spasms,  may  also  occur 
in  human  beings.  Also  paralysis  is  observed  in  man  {v.  Frankl-Hochwart) . 
Chvostek,  Jr.,  observed  for  instance  a  temporary  paralysis  in  the  ulnar  terri- 
tory after  a  spasm  that  was  long  in  duration,  which  he  attributed  to  the  long 
drawn-out  extreme  position  of  flexion.  Also  slight  ataxias  occur  in  human 
beings  as  well  as  in  animals.     Spastic  contractures  are  rare. 

In  adults,  the  sensorium  is  mostly  uninvolved,  in  children  it  is  very  fre- 
quently clouded,  although  also  in  adults,  in  the  severe  cases,  especially  in 
the  parathyroprivic  tetany  and  in  stomach  tetany,  there  may  occur  clouding 
or  indeed  complete  loss  of  consciousness. 

The  coincidence  of  epileptic  attacks  with  tetany  is  not  rare  (:'.  Frankl- 
Hochwart,  Freund,  Hirschl,  Fries,  Falta  and  Kahn,  Redlich,  et  al.).  Redlich 
has  collected  seventy-two  cases  from  the  literature.  Typical  epilepsy  may 
have  existed  for  years,  to  which  tetany  is  then  superadded,  or  epileptic  attacks 
may  occur  in  the  course  of  tetany,  or  may  set  in  simultaneously  with  it.  Espe- 
cially in  parathyroprivic  individuals  have  been  observed  severe  unilateral  or 
bilateral  epileptiform  convulsions  with  loss  of  consciousness  and  slowness 
or  absence  of  pupillary  reaction.  Such  cases  may  rapidly  come  to  a  lethal 
end;  or  the  tetany  may  altogether  subside,  and  death  follow  later  in  status 
epilepticus,  or  tetany  and  epilepsy  may  pass  over  into  a  chronic  stage  (cases 
of  Wcstphal  and  of  Redlich).  In  children  severe  eclamptic  attacks  may  enter 
into  the  course  of  tetany,  or  may  occupy  a  position  in  the  foreground.  In  the 
discussion  of  the  pathogenesis  I  shall  take  up  the  question  of  the  relation  of 
the  two  conditions. 

Finally  it  should  be  mentioned  that  in  the  severest  forms  of  tetany,  espe- 
cially in  the  parathyroprivic  forms  and  in  stomach  tetany,  myotonic  symp- 
toms are  observed  not  infrequently,  v.  Frankl-Hochwart  designates  them 
as  intention  spasms  [Intentionskrampfe] ;  they  express  themselves  in  such 
a  manner  that  on  such  an  attempted  intentional  movement  as  closure  of  the 
hand  for  instance,  the  hand  cannot  be  opened  again  for  several  seconds 


TETANY  183 

iSchuUze.    Hoffmann,    Bettmann,    Kasparek,    v.    Voss,    S chief er decker    and 
Schidtze,  V.  Orzechoivski,  et  al.). 

In  such  cases  we  also  observe  mechanical  hyper  excitability  of  the  muscles 
and  formation  of  pits  on  percussion,  indeed  even  typical  myotonic  reaction 
on  testing  wdth  the  galvanic  and  faradic  currents.  We  shall  consider  this 
more  fully  in  the  discussion  of  the  pathogenesis. 

I  have  already  mentioned  disturbances  of  the  sensorium.  In  a  series  of 
cases  psychoses  have  also  been  observed  {v.  Frankl-Hochivart,  Kraepelin, 
HirschU  and  others).  In  acute  cases,  v.  Frankl-Hochivart  several  times  saw 
typical  hallucinatory  confusion  or  deep  depression;  he  found  abnormal 
psychical  excitement  and  even  depressive  mental  attitudes,  fourteen  times 
among  thirty-seven  cases.  Erdheim  saw  characteristic  conditions  of  excite- 
ment also  in  parathyroidectomized  rats. 

Finally  it  remains  to  be  mentioned  that  in  certain  cases  a  shght  grade 
of  choked  disc  or  neuroretinitis  has  been  observed  {v.  Jaksch,  Hanke). 

I  now  come  to  the  description  of  the  behavior  of  the  vegetative  nerves  in 
this  condition.  In  the  literature  there  have  appeared  up  to  the  present 
only  a  few  scattered  references  as  to  this  question;  nevertheless  I  can  find 
ground  for  my  statements  in  the  work  I  did  in  collaboration  with  Eppinger 
and  Rudinger  and  especially  with  Fr.  Kahn;  in  addition,  there  is  a  detailed 
work  on  the  subject  of  Ibrahim.  The  vegetative  nerves  show  in  tetany 
manifestations  of  increased  excitability  on  one  hand  and  long-continued 
heightening  of  tone  on  the  other. 

Kahn  and  /  in  one  case  observed  h}perexcitability  of  the  sympathetic 
nerves  accompanying  the  vessels.  After  application  of  the  bandage  for  the 
eli citation  of  Trousseau' s  phenomenon  there  occurred  in  addition  to  this 
phenomenon,  pronounced  anemia  of  the  phalanges  of  the  third,  fourth,  and 
fifth  finger.  Since  that  time  I  have  seen  this  symptom  once,  in  the  case  of 
E.  C.  to  be  described  later  (Observation  XVIII).  In  this  case  there  occurred 
regularly  on  application  of  the  bandage  to  the  upper  arm  or  thigh,  simul- 
taneously with  Trousseaus  phenomenon,  a  pronounced  anemia  of  the  ex- 
tremity. Here  also  belongs  the  pronounced  dermographism  that  we  find  so 
extraordinarily  frequent  in  the  acute  stage  of  the  disease. 

The  electrical  hyperexcitability  of  the  vegetative  nerves  in  man  is  hard 
to  demonstrate.  On  the  other  hand,  we  may  readily  show  the  chemical 
hyperexcitability  as  seen  in  the  behavior  of  the  patient  on  the  action  of 
adrenalin  or  pilocarpine.  After  subcutaneous  injection  of  adrenalin  in  the 
acute  stage  of  tetany  there  occurs  almost  regularly  an  abnormally  strong 
action  on  the  blood-pressure,  on  the  heart  action,  on  the  contraction  of  the 
vessels  of  the  skin,  and  also  on  the  tetanic  spasm.  The  increase  in  the 
blood-pressure  and  the  pulse  rate  was  especially  rapid.  To  it  were  often 
added  extreme  paleness  of  the  face  and  the  skin  of  the  entire  body,  strength- 
ening of  the  heart  action,  subjective  cardiac  palpitations,  and  even  extra- 


184  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

systoles.  In  almost  all  cases  there  was  an  acute  exacerbation  of  the  tetanic 
conditions,  together  with  paresthesias  or  spasms.  In  the  declining  stage 
of  the  disease,  all  these  manifestations  were  very  much  less  pronounced. 

An  abnormally  strong  vascular  action  of  the  adrenalin  could  also  be 
demonstrated  on  the  parathyroidectomized  dog. 

Later,  in  the  consideration  of  the  metabolism,  I  will  take  up  the  question 
of  the  glycosuric  action  of  adrenalin  in  tetany. 

Again,  the  sensitiveness  to  pilocarpine  is  essentially  increased  in  the 
acute  stage  of  tetany.  There  occurs  abnormally  strong  outbreak  of  sweat 
or  salivation,  together  with  flow  of  tears,  initial  contraction  of  the  erectores 
pilorum  muscles  (gooseflesh) ,  later  marked  reddening  of  the  skin  of  the  body 
with  sensation  of  heat  and  rushes  to  the  head,  abnormal  increase  of  the 
secretion  of  gastric  juice  and  relaxations  of  stomach  tonus;  further,  symptoms 
that  we  do  hardly  see  on  the  administration  of  this  pilocarpine;  symptoms 
such  as  nausea,  diarrhea,  urinary  and  rectal  pressure.  Also  pilocarpine 
induces  frequent  tetanic  spasms  in  the  various  muscular  territories.  The 
manifestations  of  an  increased  tonus  in  the  vegetative  nerves  in  the  first  stage 
of  tetany  are  of  very  manifold  nature.  Here  I  follow  almost  verbatim  the 
expositions  on  the  subject  in  the  work  of  Kahn  and  myself. 

Spasmodic  conditions  of  the  smooth  ciliary  muscle  seem  to  occur  very 
rarely.  Kunn  and  Fr.  Midler  saw  mydriasis  in  the  attack  (spasm  of  the 
dilatator  papillae  ?).  Fcer  and  also  Eschericli  observed  transitory  differences 
in  the  size  of  the  pupils,  that  Feer  regarded  as  spasmodic  conditions.  A. 
Fucks  saw  during  the  attack  appreciable  diminution  in  the  time  of  pupillary 
reaction.  Finkelstein  saw  pupillary  rigidity.  Ibrahim  saw  pupillary 
differences  in  one  case  (unilateral  spasm  of  the  dilator  pupillae).  In  this 
case  the  neck,  pharyngeal  and  eye  muscles  were  especially  involved  in  the 
spasm,  thus  simulating  the  picture  of  a  meningitis.  The  cerebrospinal  fluid 
was  clear,  however. 

Little  is  known  as  to  lachrymation  in  tetany;  evidence  as  to  the  proba- 
bility of  its  occurrence  is  furnished  in  one  case  only,  that  of  Kalin  and  myself. 
Here  there  existed  slight  redness  of  the  conjunctiva  and  there  was  often  an 
increase  in  the  lachrymation  simultaneously  with  the  exacerbation  of  the 
tetany,  as  well  as  an  increased  flow  of  saliva. 

^Marked  sweats  are  frequently  found  in  the  acute  stage  of  tetany. 

In  tetany  it  is  diflicult  to  refer  changes  in  the  type  of  breathing  to  al- 
terations in  the  tonus  of  the  smooth  musculature  of  the  bronchi,  as  we  must 
not  overlook  what  part  spasms  of  the  diaphragm  and  of  the  intercostal 
muscles  eventuall}-  phi}'  in  its  production.  Ibrahim,  Finkelstein  and  Popper 
report  cases  of  tach}'pnea.     We  saw  dyspnea  occur  very  frequently. 

Disturbances  of  the  action  of  the  heart  seem  to  be  very  frequent.  Kahii 
and  /  could  observe  in  almost  all  cases  in  the  acute  stage  strengthening  of 
the  cardiac  action,  loud  sounds  at  the  apex,  and  even  accentuated  second 


TETANY  155 

pulmonic  sound,  in  one  case  an  accentuated  aortic  second.  To  this  is  added 
lability  of  the  heart  action,  in  other  words,  slight  tachycardia  on  psychical 
excitement  and  abnormally  high  pulse  rate  on  working.  Complaints  as  to 
cardiac  palpitations  are  frequent.  In  two  cases  we  observed,  toward  the 
end  of  the  stay  at  the  hospital,  occurrences  of  mitral  systolic  murmurs 
that  surely  were  not  there  previously. 

Very  noteworthy  are  the  statements  of  Ibrahim.  This  author  saw  sudden 
death  without  spasm  of  the  glottis  in  three  cases  of  tetany  of  sucklings, 
without  signs  of  suffocation  showing  at  autopsy.  Signs  of  status  thymico- 
lymphaticus were  in  these  cases  absent  or  only  slightly  developed.  In  two 
of  these  cases  the  heart  was  relaxed  in  dilatation.  In  the  third  case  the  right 
ventricle  was  relaxed,  the  left  unusually  hard  and  forcibly  contracted. 
Ibrahim  thought  of  tetany  of  the  heart,  probably  called  forth  by  vagal  or 
sympathetic  excitement.  We  do  not  as  yet  know  how  far  abnormal  condi- 
tions of  excitability  of  the  autonomous  heart  ganglia  or  heart  regulating 
nerves  are  responsible  for  the  manifestations  mentioned. 

In  tetany  of  adults  manifestations  on  the  part  of  the  vascular  apparatus 
are  very  pronounced.  In  the  acute  stage  all  tetanies  have  pronounced  vaso- 
motor disturbances.  They  all  look  pale,  in  spite  of  the  fact  that,  as  we 
shall  see  later,  blood  counts  show  high  figures  for  red  cells  and  a  hemoglobin 
value  not  lowered.  Emotions  often  call  forth  abnormally  intensive  varia- 
tions of  tonus  in  the  vessels;  and  the  edematous  swellings  that  are  observed 
not  infrequently  are  to  be  regarded  as  angiospastic  manifestations.  Ibrahim 
saw,  in  a  suckling  suft'ering  with  tetany,  edema  of  the  legs,  with  kidneys  in- 
tact, and  Kahn  and  /  several  times  saw  marked  edema  of  the  skin  over  the 
metacarpo-phalangeal  joints  after  severe  attacks.  Cnrschmann  described 
pronounced  angiospastic  manifestations,  vascular  spasms  of  the  fingers 
and  toes.  Heat  relieved  the  attacks.  Here  too  would  belong  the  char- 
acteristic puffiness  of  the  face  which  was  first  described  by  v.  Frankl-Hoch- 
wart  and  which  we  have  also  frequently  observed.  The  face  is  pale  but  does 
not  possess  the  livid  coloration  that  tends  to  appear  in  myxedema. 

I  now  take  up  the  question  of  the  blood  picture  in  tetany,  as  it  stands  in 
intimate  relationship  with  the  manifestations  on  the  part  of  the  vascular 
apparatus.  Until  the  appearance  of  our  work,  the  statements  as  to  blood 
changes  in  tetany  were  concerned  only  with  cases  of  so-called  stomach  tetany. 
In  isolated  cases  there  has  been  observed  appreciable  increase  in  the  number 
of  red  cells,  or  increase  in  the  specific  gravity  {F.  M idler,  Fleiner,  Kuckeiu, 
also  ourselves),  and  attempts  had  been  made  to  refer  these  to  the  organism's 
poverty  in  water,  that  might  have  been  brought  about  by  deficiency  in 
absorption  on  account  of  pyloric  stenosis,  or  the  vomiting  of  large  amounts 
of  gastric  juice.  Our  investigations  showed  decisively  that  this  polyglobulia 
is  directly  a  tetany  symptom.  Above  all,  it  could  be  shown  that  in  the  case 
of  "stomach  tetany"  this  polyglobulia  existed  only  in  the  acute  stages,  and 


1 86  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

with  the  dedine  of  the  tetany  it  again  made  way  for  normal  relations;  the  in- 
vestigations also  showed  that  the  polyglobulia  may  be  for  a  time  appreci- 
ably increased  during  an  acute  attack,  in  one  case  rising  from  5,106,000  to 
7,808,000  red  cells;  finally,  the  investigations  showed  that  in  the  cases  of 
occupation  tetany  the  red-cell  count  is  higher  during  the  acute  stages,  and 
that  it  is  temporarily  raised  even  higher  during  an  acute  attack.  As  ex- 
ample, I  cite  the  following  case: 

Observation  XVIII. — C.  E.  Entered  the  clinic  May  14,  1912.  Carpenter,  forty 
years  old.  For  about  four  years  the  patient  felt  a  striking  sensation  of  fatigue  in  the 
arms  and  legs,  especially  after  heavy  work  and  after  long  walks.  He  also  had  par- 
esthesias in  the  arms  and  legs  (formication,  "going  to  sleep"  of  the  left  leg).  For  two 
years  slight  gastric  disturbances,  consisting  in  brief  spasmodic  pains,  and  in  acid  eructa- 
tions, sometimes  associated  with  vomiting.  For  the  last  year,  the  patient  has  felt  quite 
well. 

Two  days  ago  he  suddenly  experienced  nausea,  acid  eructations,  vomiting,  and  a  colicky 
pain  in  the  region  of  the  stomach.  Some  hours  later  he  experienced  spasmodic  drawing 
together  of  the  hands  (according  to  the  description,  the  typical  obstetrician's  position), 
and  formications  in  the  tips  of  the  fingers  and  twitchings  of  the  muscles  of  the  face. 
Later  there  were  also  spasms  of  the  lower  extremities,  which  became  quite  rigid.  The 
spasms  seem  to  have  lasted  three  to  four  hours.  The  patient  was  conscious  throughout 
the  spasm.     Since  then  the  spasms  have  been  repeated  several  times. 

Rather  strong  potator.     Inclination  to  bronchitides. 

Rather  vigorous,  large  patient,  pale  color  of  the  face,  facial  expression  as  if  he  were 
going  to  cry,  skin  moist,  apical  dullness  on  the  left,  vesicular  murmurs  sharpened,  at 
places  rhonchial  and  whistling  murmurs.  Cardiac  findings  normal.  Liver  two  finger- 
breadths  below  the  margin  of  the  ribs.     Very  well  pronounced  dermographism. 

Chvostek  I  and  //  strongly  positive;  also  the  frontal  muscles  twitch  on  application  of 
the  test;  Trousseau  markedly  positive,  Hoffman  markedly  positive,  Schlesinger  markedly 
positive. 

Electrical  examination  Ulnar  Facial 

C.C.C.  i.o  0.6 

An  C.C.  2.5  1.8 

An  O.C.  3.4  1.0 

C.C.Te.  8.0  1.2 

An  C.Te.  not  attainable  not  attainable 

Mechanical  hyperexcitability  of  the  muscles  very  pronounced.  Idiomuscular  ridges 
make  their  appearance. 

Patellar  reflexes  markedly  exaggerated,  suggestion  of  a  patellar  clonus. 

Coarse  tremor  of  the  fingers. 

Blood-pressure  {Gartner),  125. 

In  urine  traces  of  albumin,  reactions  for  urobilin  and  urobilinogen  markedly  positive. 

Tubercle  bacilli  in  the  sputum. 

Increase  of  temperature  up  to  37.3°. 

May  14. — During  the  day  and  also  during  the  preceding  night  many  severe  tetanic 
spasms  in  the  upper  and  lower  extremities,  that  always  lasted  for  several  hours. 

On  elicitation  of  Trousseau's  phenomenon  by  means  of  the  bandage  fibrillary  con- 
tractions occur  in  the  musculature  of  the  arms  or  feet  respectively.  Together  with  the 
spasm  there  regularly  appears,  on  application  of  the  bandage,  a  pronounced  anemia  of  the 
extremity  in  question. 


TETANY  187 

May  15. — Severe  attack  this  morning,  at  10  o'clock,  during  which  blood  was  with- 
drawn from  the  ear.     The  blood  is  dark  red. 

Erythrocytes.  6.500.000. 

Leucocytes,  4200,  of  which: 

Polymorphonuclear  neutrophiles.  63  per  cent. 

Large  mononuclear  cells,  36  per  cent. 

Eosinophiles,  i  per  cent. 

May  16. — Blood  findings  during  the  attack-free  interval. 

Erythrocytes,  5,600,000. 

Trousseau  positive;  after  the  decline,  the  patient  complained  of  severe  bone  pains  in 
the  extremit}'  affected. 

May  20. — Xo  attack  since  the  i6th.  Face  still  slightly  swoUen^  facial  expression  still 
somewhat  as  if  the  patient  were  going  to  weep. 

May  22. — Erj^throcytes,  5,200.000. 

May  24. — Trousseau  can  no  longer  be  elicited. 

May  25-31. — Patient  feels  well,  no  paresthesias;  he  has  gained  as  much  as  5  kg., 
appetite  excellent,  no  gastric  disturbances. 

In  a  case  reported  by  Falta  and  Kahn  the  following  values  were  found : 
At  the  beginning  of  the  observation  about  4,000,000  erythrocytes  and  9 
gm.  hemoglobin.  Three  weeks  later  during  a  long-continued  severe  attack 
7,808.000  erythrocytes  and  14.86  gm.^  hemoglobin.  The  next  day,  during 
a  period  of  almost  free  attacks  there  was  5.106,000  erythrocytes.  Later 
after  amelioration  of  the  spasms  4.160,000.  This  was  a  case  of  tetany 
in  the  course  of  a  Reichmann^ s  disease.  In  another  case  (Observation  XXIII) 
that  I  report  below,  we  likewise  see  a  distinct  agreement  between  the  varia- 
tion of  the  erythrocyte  count  and  the  tetanic  condition.  I  would  suppose 
that  the  behavior  of  the  erythrocytes  furnishes  a  good  criterion  for  the 
course  of  the  disease,  just  as  the  leucocyte  formula  does  in  Basedow's  disease. 

In  dogs,  also,  we  have  seen,  after  parathyroidectomy,  the  count  of  erythro- 
cytes in  the  acute  stage  rise  to  7,000,000.  Such  polyglobuhas  occurring  dur- 
ing the  acute  stage  can  be  explained  in  no  other  way  than  that  they  are 
due  to  vascular  spasm,  analogous  to  those  polyglobulias  which  are  observed 
after  injection  of  adrenalin  (Bertelli,  Falta,  and  Scku'eeger).  But  one  is  not 
justified  in  assuming,  on  this  account,  that  during  the  tetanic  attack  there  is 
an  increased  production  of  adrenalin;  we  should  rather  suppose  that  in  analogy 
with  all  other  conditions  of  excitement  in  tetany  the  seat  of  the  hyperexcita- 
bihty  is  to  be  found  in  the  ganglia.  We  have  noticed  no  increase  of  blood- 
pressure  during  the  attack,  which  however  does  not  speak  against  our 
supposition — for  vascular  spasm  need  not  occur  in  all  portions  of  the  body 
simultaneously  and  thus  an  equalization  of  blood  pressure  may  occur  very 
readily.  The  polyglobulia  of  the  so-called  stomach  tetany  is  to  be  explained 
in  the  same  way. 

The  leucocyte  count  in  tetany  is  mostly  normal.     Leastwise  in  individual 

1  In  German  edition  "per  cent.'"  This  has  been  corrected  to  "gm.''  on  reference  to  the 
original  article. — Editor. 


1 88  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

cases,  we  saw,  during  severe  attacks,  transitory  hyperleucocytosis  up  to 
19,000.  Differential  counts  of  the  leucocytes  showed,  in  the  great  majority 
of  cases,  a  rather  distinct  lymphocytosis  or  a  relative  and  absolute  diminu- 
tion of  the  neutrophilic  cells.  In  these  cases  there  also  were  found,  for  the 
most  part,  swellings  of  the  lymph  glands  at  the  portions  of  the  body  accessible 
to  palpation,  enlargement  of  the  tonsils  and  papillae  of  the  base  of  the  tongue, 
hence  a  slight  status  lymphaticus. 

With  more  exact  investigation,  there  could  also  be  demonstrated  in  the 
great  number  of  cases  of  tetany  slight  or  severe  disturbances  in  the  function 
of  the  gastrointestinal  tract.  In  this  connection  we  could  distinguish  two  cate- 
gories of  cases.  In  one  the  tetany  develops  in  individuals  who  have  been 
sick  for  a  long  time  with  gastric  and  intestinal  complaints,  especially  with 
those  which  lead  to  a  high-grade  stagnation  of  the  gastric  or  intestinal  con- 
tents. To  this  group  I  shall  refer  more  in  detail  in  the  consideration  of 
the  individual  forms  of  tetany.  In  the  second  category  the  gastroin- 
testinal disturbances  occur  at  or  after  the  outbreak  of  the  tetany.  Many 
such  cases  have  been  observed  by  Kahn  and  myself.  Of  such  disturbances 
I  would  mention:  First,  a  certain  hyperexcitability  which,  as  already 
mentioned,  manifests  itself  in  the  experiment  with  pilocarpine  in  an  ab- 
normally marked  laxity  of  the  stomach  and  in  a  very  pronounced  stratifica- 
tion of  the  gastric  contents,  eventually  in  tenesmus  and  diarrheas.  Second, 
manifestations  of  increased  secretion  of  the  gastric  or  intestinal  glands;  in 
certain  cases  there  is  found  for  example  a  slight  grade  of  hyperchlorhydria, 
such  as  has  been  described  by  Jonas  and  Rudinger.  On  increased  secretional 
processes  in  the  intestinal  tract  may  depend  the  diarrheas  we  observed  so 
frequently.  In  many  cases  the  tetany  is  ushered  in  with  diarrheas  or 
vomiting. 

As  example  I  cite  the  following: 

Observation XIX. — A.  W.  (Case  VII  oiFalta  and  Kahn),  twenty-seven-year-old  woman 
from  Vienna.  Entered  the  first  medical  clinic  March  16,  1909.  Marked  chlorosis  at 
the  age  of  sixteen.  Menstruation  from  the  age  of  eighteen  on,  regular.  Three  normal 
confinements.  Three  days  ago  suffered  with  severe  pains  in  the  abdomen,  that  were 
associated  with  fever,  eructations,  and  constipation.  On  the  next  morning  typical  tet- 
anic spasms  in  the  upper  extremities,  hands  in  the  obstetrician's  position,  flexion  at  the 
elbows,  upper  arms  drawn  to  the  body.  At  least  six  such  attacks  each  of  about  five  min- 
utes' duration.  The  spasms  were  painful.  The  galvanic  excitability  was  increased. 
Rapid  recovery. 

Still  more  instructive  is  the  following  case,  in  which  the  gastric  dis- 
turbance set  in  at  the  same  time  as  the  tetanic  spasms: 

Observation  XX. — ^L.  E.  (Case  VIII  oi  Fatta  and  Kahn),  twenty-year-old  woman  from 
Vienna.  Entered  the  first  medical  clinic  on  March  23,  191 1.  One  normal  confinement. 
Present  illness  began  six  days  ago  with  severe  pains  in  the  back  and  hypogastrium, 
with  the  vomiting  of  green-colored  masses  of  bitter  taste,  and  a  painful  spasmodic  attack 
affecting  the  hands  and  legs.  The  hands  were  in  typical  obstetrician's  position.  Two 
days  later  again  severe  pains  in  the  abdomen,  with  vomiting,  associated  with  typical  attack 


TETANY 


iperature  as  Jiigh  as  38  .    Indican  much  increased.     Rapid  recovery. 
In  other  cases  the  gastric  disturbances  occur  later,  and  are  made  worse 
by  a  la  er  exacerbation  of  the  tetany.     We  find  likewise  that  in  the  cases  of 
he  first  category  the  gastrointestinal  disturbances  may  increase  markedly  at 
the  time  that  the  tetany  is  added  to  the  clinical  picture 


Fig.  26.— Tetany  face  (Observation  XXI). 


en^nt   "''"^  T"''  ""  '"'"  ''-'  """  fl"°™5™P<=.-  there  is  an  abnormally  rapid 
emptying  of  the  stomach.     In  some  cases  there  is  a  marked  pyloric  spaTm 

that   b'r     T''  ''''  '^"'^  '°  ^""'^  ''"^'^"»  °f  ">^  ^'°»-h-     Th~ 
that  belong  here,  which   Kah„  and  ,nyself  have   reported,    are   those  o 
the  first  category,  m  which  gastric  disturbances  existed  previously      It  is 
probable  that  the  tetany  increases  the  pyloric  spasm,  Tr  in  many  cases 


igo 


THE    DISEASES    OF    THE    PARATHYROID    GLANDS 


directly  brings  it  about.     A  short  time  ago,  I  saw  also  a  case  of  typical 
occupation  tetany  that  showed  the  same  thing.     The  report  of  it  follows: 

Observation  XXI. — B.,  seventeen  years  old,  shoemaker.  Entered  the  clinic  Jan.  14, 1913. 
First  attack  of  tetany  in  winter  of  191 1.  The  convulsions  then  lasted  with  interruptions 
throughout  the  winter,  disappearing  only  in  April.  Throughout  the  summer,  the  patient 
felt  quite  well;  two  days  ago  spasms  reappeared,  especially  in  the  upper  extremities,  and  to 
it  were  added  formications.     The  sj-mptoms,  varying  in  intensity,  have  lasted  until  to-day. 

The  patient  shows  the  typical  crying  facial  expression  of  the  tetanic.  There  exists 
great  vasomotor  excitability.  All  the  tj^pical  symptoms  of  tetany  are  present.  The 
galvanic  excitability  is  much  increased.  The  examination  of  the  blood  shows  6,250,000 
erythrocytes.  There  exist  painful  spasms,  especially  in  the  upper  extremities,  that  are 
often  repeated  throughout  the  day.     Temperature  as  high  as  37.5°. 

Jan.  18. — For  three  days  no  spasmodic  attacks,  the  electrical  excitability  is  less  in- 
creased; in  blood,  4,870,000  erythrocytes.  Chvostek's  and  Trousseau's  phenomena  no 
more  elicitable. 


Fig.   27. — Spasm  of  the  stomach  in  tetany  {Falta  and  KaJin,  Ztsch.  f.  klin.  ^led.,  Bd.  LXXIV)- 


Jan.  23. — Fresh  spasms,  the  symptoms  of  tetany  present  once  more,  5,820,000  ery- 
throcytes. 

Jan.  24. — X-ray  examination  two  hours  after  breakfast  shows  a  dilated  stomach  filled  to 
a  marked  degree  with  fluid;  it  reaches  to  three  finger-breadths  below  the  umbilicus;  there 
exists  lengthened  time  for  emptying  of  the  stomach,  in  short,  signs  of  a  hypersecretion  with 
pyloric  stoiosis. 

Jan.  31. — Chvostek  still  positive,  more  spasms,  6.400,000  crythrocj'tes. 

Feb.  6. — No  spasms  any  more,  but  there  still  exists  paresthesias.  Chvostek  and 
Trousseau  negative. 

From  now  on  the  tetanic  sj'mptoms  decline,  the  count  of  erythrocytes  becomes  normal 
(4,500,000-4,800,000),  the  X-ray  examination  of  the  stomach,  that  has  been  taken  three 
times  in  the  course  of  the  last  two  weeks,  now  always  shows  normal  relations;  after  a 
breakfast  the  X-rays  show  that  the  stomach  reaches  to  two  finger-breadths  below  the 
umbilicus.     Peristalsis  and  time  of  emptying  are  now  normal. 

In  this  case,  therefore,  is  to  be  found  an  "attack''  of  pylorospasm  and 
hypersecretion  and  consecutive  dilatation  of  the  stomach  occurring  in  the 


TETANY 


191 


.Fig.  28.— Spasm  of  the  stomach  in  tetany  {aitei Falta  and  Kahn,  Ztsch.  f.  klin.  Med.,  Bd.LXXIV). 


192  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

acute  stage  of  tetany.  Also  Ibrahim  is  of  the  opinion  that  the  pylorospasm 
can  occur  in  the  course  of  a  tetany  of  childhood. 

Especially  significant  for  this  question  are  two  observations  that  have 
been  reported  by  KaJin  and  myself.  I  would  therefore  go  into  the  question 
more  accurately  at  this  point.  In  the  one  case  (Observation  XXII — Case 
18  of  Falta  and  Kahn),  X-ray  examination  at  the  time  that  only  slight  signs 
of  tetany  existed  showed  an  elongated  but  otherwise  normal  stomach. 
On  a  later  examination,  during  an  acute  exacerbation  of  the  tetany,  there 
was  found  a  retraction  of  the  greater  curvature,  completely  the  picture  of 
an  hour-glass  stomach  (see  Fig.  27).  The  tetanic  spasms  rapidly  decreased 
in  intensity,  the  stomach  assuming  normal  relations  after  a  few  days.  In 
the  case  there  were  no  grounds  for  the  assumption  of  an  ulcus  ventriculi. 
In  a  second  case  (Observation  XXIII — Case  17  of  Falta  and  Kahn)  the 
stomach,  as  found  on  X-ray  examination  at  the  time  of  an  acute  exacerbation 
of  the  tetany  and  indeed  during  an  attack,  was  small,  markedly  contracted, 
divided  in  two  parts  like  an  hour-glass  stomach;  in  addition  there  was 
insufficiency  of  the  pylorus;  there  was  present  therefore  a  total  spasm  of  the 
stomach,  that  affected  also  the  longitudinal  musculature.  At  the  next 
examination,  this  phenomenon  occurred  again,  gradually  decreasing  in 
intensity,  however,  with  the  amelioration  of  the  tetany;  and  later,  when  the 
tetany  had  disappeared  entirely,  the  stomach  showed  normal  relations  on 
X-ray  examination  (see  Fig.  28).  We  regarded  these  manifestations  as 
conditions  of  tetanic  spasms. 

Also  in  thyroprivic  animals  I  several  times  observed  that  the  spasm 
was  ushered  in  with  vomiting  and  bowel  movement. 

All  observations  detailed  point  to  the  fact  that  in  the  acute  stage  of 
tetany  the  gastrointestinal  tract  may  show  symptoms  of  increased  ex- 
citability and  a  heightened  tonus,  which  later  may  increase  up  to  a  spas- 
modic condition.     To  which  are  added  heightening  of  the  secretory  processes. 

Ibrahim  further  describes,  in  the  case  of  suckling  tetany,  spasm  of  the 
sphincter  of  the  bladder  that  led  to  marked  retention  of  urine,  and  mentions 
similar  observations  of  Sachs,  Escherich  and  Hagenbach-Burckhardt.  v. 
Frankl-Hochwart  had  mentioned  still  earlier  a  retention  of  urine  in  tetany  of 
adults.  Ibrahim  further  assumes  involvement  of  the  sphincter  ani  in  the 
tetanic  spasms  as  he  often  observed  in  suckling  tetany  an  intense  gaseous 
distention  of  the  abdomen  (flatulent  colic).  After  introduction  of  an  in- 
testinal tube  there  were  emptied  large  amounts  of  gas — or  even  spontaneously 
there  occurred  an  "explosion-like  expulsion  of  flatus  with  frequent  clonic 
twitchings  of  the  abdominal  muscles."  Also  Kocppe  had  already  supposed, 
as  Ibrahim  states,  that  the  internal  sphincter  became  contracted  in  the 
eclamptic  attack. 

.Finally  we  mention  the  disturbances  of  the  regulation  of  heat.  In  para- 
thyroprivic  dogs  there  often  occur,  during  attacks,  increases  in  temperature; 


TETANY  193 

in  very  intense  spasms  we  even  observed  on  several  occasions  values  signify- 
ing hyperpyrexia.  Such  disturbances  of  heat  regulation  also  occur  in  human 
tetany.  In  the  attack-free  interval,  the  body  temperature,  as  v.  Jaksch  and  v. 
Frankl-Hochwart  have  emphasized,  is  often  abnormally  low.  In  thirty-five 
observations  on  acute  cases  v.  Jaksch  saw  more  or  less  fever  at  the  beginning  of 
the  disease  nine  times.  Kahn  and  my  observations  agree  with  these.  We 
frequently  saw  with  the  acute  stage  temperature  as  high  as  37.8°,  in  one 
case  up  to  38.5°,  without  exact  investigation  affording  any  ground  that 
there  was  any  cause  for  the  increase  of  temperature  other  than  the  tetany. 
Later,  after  decline  of  the  tetany,  the  temperature  sank  to  normal  or  slightly 
subnormal  values.  In  certain  cases  we  found  in  the  acute  stage  transitory 
rises  of  temperature  after  the  injection  of  substances  that  otherwise  do  not 
tend  to  induce  fever  (antithyroidin  (Mobius),  pituitrium  glandulare  oi  Parke, 
Davis  b'Co.).  This  points  to  an  especial  lability  of  the  regulation  of  heat. 
One  could  be  tempted  to  regard  the  increase  of  temperature  in  the  sense  of 
those  authors  who  consider  idiopathic  tetany  as  an  infectious  disease.  The 
fact  that  it  is  found  to  still  higher  degrees  in  experimental  thyroprivic  tet- 
any has  led  Kahn  and  myself  to  the  assumption  that  it  is  probably  the  ex- 
pression of  a  condition  of  excitability  of  the  vegetative  nerves. 

Summarizing  again  all  observations  that  can  be  advanced  for  the  vegeta- 
tive organs,  we  find  that  in  the  acute  stage  of  tetany  the  hyperexcitability  or 
the  abnormal  conditions  of  irritability  are  not  limited  throughout  to  the  central 
nervous  system  and  to  the  peripheral  nerves,  hut  that  they  involve  also  the  vegeta- 
tive nervous  system.  With  the  decline  of  the  acute  tetanic  condition  there 
also  occurs  a  decline  of  the  condition  of  irritability  of  the  vegetative  nerves. 

Also  the  metabolism  in  tetany  shows  alterations. 

Disturbances  in  the  carbohydrate  metabolism  are  almost  constant  in  the 
tetanic  dogs.  First  a  few  remarks  as  to  the  glycosuric  action  of  adrenalin 
in  tetany.  In  the  thyroidless  dog  it  is  known  that  the  glycosuric  action  of 
adrenalin  is  reduced.  In  dogs  that  have  had  only  their  parathyroids  re- 
moved it  is  mostly  increased,  so  far  as  a  tetanic  spasm  is  not  induced  by  the 
injection  (Eppinger,  Falta,  and  Rudinger) .  In  the  idiopathic  human  tetany 
Rudinger  and  /  never  found  in  the  acute  stage  glycosuria  following  injec- 
tion of  adrenalin;  but  on  the  contrary,  as  already  mentioned,  almost  always 
a  strong  reaction  of  the  cardiovascular  apparatus.  This  dissociation  of 
the  action  of  adrenalin  has  its  foundation  chiefly  in  the  increase  of  sugar 
consumption  through  the  enormous  vasoconstriction  and  eventually  in 
the  attack  induced  by  means  of  injection.  In  the  declining  stage  of  tetany 
we  find,  contrariwise,  frequently  a  distinct  glycosuric  action  due  to  adrenalin. 

In  parathyroidectomized  dogs  the  assimilation  limits  for  dextrose  are 

regularly  reduced.     Falkenburg  and  R.  Hirsch,  and  also  Frank  P.  Underhill 

and  Tadasu  Saiki,  found  this  after  thyroparathyroidectomy  and  referred  it 

to  the  absence  of  the  thyroid  gland.     This,  however,  leads  to  a  heightening 

13 


194  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

of  the  tolerance  boundary.  According  to  the  experiments  of  Eppinger, 
Rudinger,  and  myself  the  glycosuria  after  thyroparathyroidectomy  depends 
on  the  absence  of  the  parathyroids.  In  a  dog  almost  completely  parathy- 
roidectomized  we  found  that  when  a  diet  rich  in  starch  was  administered 
veen  large  amounts  of  sugar  would  appear  in  the  urine  for  a  long  time. 
After  the  extirpation  of  the  pancreas  and  three  parathyroids  we  found  in 
many  experiments  a  higher  D  to  X  quotient  than  could  be  obtained  on 
extirpation  of  the  pancreas  alone.  In  human  beings  ill  with  tetany  we 
never  found  reduction  of  the  assimilation  limits  for  dextrose,  and  Kahn  and 
I  can  adduce  an  observation  that  shows  that  also  in  human  beings  the  in- 
sufficiency of  the  function  of  the  parathyroids  exercises  an  indirect  in- 
fluence on  the  function  of  the  pancreas.  In  a  case  of  Basedow's  disease 
complicated  with  tetany  the  test  for  alimentary  glycosuria  immediately 
after  the  tetanic  attack  yielded  4.1  gm.  of  sugar.  Later,  after  the  acute 
tetany  had  subsided,  many  tests  for  alimentary  glycosuria  resulted  negative. 
In  the  literature  is  found  only  a  statement  of  Miller  that  he  observed  transi- 
tory glycosuria  after  an  attack  of  tetany. 

MacCalhim  and  Vogtlin,  and  also  we,  saw  the  protein  exchange  in  para- 
thyroidectomized  dogs  appreciably  increased.  There  do  not  exist  similar 
investigations  on  human  beings.  There  also  occur  regularly  disturbances 
of  the  intermediate  protein  exchange.  MacCallum  and  Vogtlin  found  in 
thyroparathyroprivic  dogs  increase  of  the  elimination  of  ammonia  in  the 

NH3N 

urine  and  of  the  quotient  — Vj — ,  and  in  addition  increased  creatinin  elimi- 
nation. In  human  idiopathic  tetany  Kahn  and  /  found  in  the  acute 
stage  the  elimination  of  ammonia  for  the  most  part  relatively  and  absolutely 
increased.  The  amino-acid  fraction  was  for  the  most  part  normal;  on  the 
contrary,  the  peptid-N  in  our  experiments  was  often  even  appreciably 
increased.  Administration  of  glycocoll  increased  this  value  mostly  only 
unessentially.  Immediately  after  the  decline  of  the  acute  tetany  this  value 
for  the  peptid-X  was  mostly  still  high,  but  distinctly  lower  than  in  the 
acute  stage,  or  it  had  already  become  normal.  Also  the  heightening  of  the 
ammonia  value  can  apparently  outlast  for  some  time  the  acute  stage.  The 
findings  described  are  to  be  distinguished  from  those  in  lesions  of  the  liver  in 
that  in  the  latter  the  amino-acid-N  is  ordinarily  increased  as  much  as,  or 
even  more,  than  the  peptid-X",  and  the  administration  of  glycocoll  almost 
always  causes  an  increase  of  these  factors.  Perhaps  these  disturbances  of 
the  intermediary  metaboHsm  in  tetany  are  the  expression  of  a  condition  of 
nervous  hyperirritability  of  the  liver. 

Systematic  investigations  as  to  the  gaseous  metabolism  in  tetany  have  as 
yet  not  been  made.  That  the  exchange  of  calories  in  the  acute  stage,  and 
especially  in  the  severe  attack  is  markedly  increased,  needs  no  especial  in- 
vestigation.    More  interesting  would  be   the  investigation  of   the  funda- 


TETANY  195 

mental  exchange  in  chronic  tetany.  Partially  parathyroidectomized  animals 
often  show  a  severe  cachexia;  and  often  in  human  idiopathic  tetany,  cachetic 
manifestations  later  make  their  appearance  {v.  Frankl-Hochwart) .  The  cases 
of  relapsing  tetany  that  Kakn  and  /  observed  all  showed  more  or  less  dis- 
tinct signs  of  cachexia  (see  later  the  relations  to  the  thyroid  gland).  Here 
there  must  be  a  profound  disturbance  of  metabolism,  as  has  been  mentioned 
by  Segale  and  others. 

The  behavior  of  the  calcium  metaholism  in  tetany  has  been  much  studied. 
Stimulating  were  the  observations  of  Sabbatani  and  Loeb.  Sabbatani  found 
that  application  of  calcium  salts  to  the  surface  of  the  brain  reduced  the 
excitability,  application  of  sodium  salts  increased  it;  Loeb  found  that  sub- 
stances that  precipitate  calcium  heightened  the  excitability  of  the  nerves. 
This  holds  true  also  for  the  vegetative  nerves  {R.  Chiari  and  A.  Frohlich). 
MacCallum  and  Vdgtlin  as  well  as  Parhon  and  Orechie  have  tried  to  influence 
favorably  the  tetanic  spasms  of  parathyroidectomized  dogs  by  the  subcu- 
taneous or  peroral  administration  of  calcium.  Magnesium  salts  work  directly, 
as  do  the  calcium  salts,  but  show  in  addition  strong  toxic  action.  Potassium 
salts  increase  the  irritability.  Quest  had  already  stated  before  this  that  the 
brain  of  new-born  infants,  which  is  relatively  slightly  excitable,  is  very 
rich  in  calcium,  but  that  later  the  calcium-contents  of  the  brain  reduces. 
He  further  states  that  diet  poor  in  calcium  makes  the  animal  hyperexcitable, 
and  that  the  brains  of  children  after  they  have  died  of  tetany  are  very 
poor  in  calcium.  MacCallum  and  Vdgtlin  found  the  calcium-contents  of 
the  brain  of  parathyroidectomized  dogs  lowered,  as  well  as  those  of  the  blood. 
The  elimination  of  calcium  through  the  urine  and  feces  was  increased.  This 
last  fact  was  also  found  by  us.  The  same  was  also  observed  by  Cattaneo. 
Neurath,  who  estimated  the  so-called  active  calcium  in  the  blood  of  children 
with  tetany  by  Wrighfs  method,  found  very  low  values.  Investigations  as 
to  the  calcium  balance  in  children  with  tetany  frequently  show  increased 
elimination  of  calcium  (L.  V.  Iddo  dJiA  Sarle,  and  others).  Aschenheim  has 
recently  pointed  out  that  there  does  not  exist  so  much  an  absolute  calcium 
poverty  of  the  tissues  as  there  does  [an  increase  of]  the  relation  of  alkalies  to 
earthy  alkalies.  He  found  in  children  who  had  died  of  spasmophilia  an 
increase  of  this  quotient  just  as  in  parathyroidectomized  dogs.  Finkel- 
stein  and  Rosenstern  arrived  at  similar  views.  According  to  Rosenstern  the 
administration  of  common  salt  to  children  brings  forth  anodal  hyperexcita- 
bility,  and  indeed  even  laryngospasm. 

Experimental  investigations  show  also  that  the  function  of  the  para- 
thyroids influences  bone  formation.  Morel  and  Canal  found  in  parathy- 
roidectomized dogs  that  the  healing  of  fractures  is  delayed  and  the  callus 
formation  slowed.  Erdheim  showed  that  such  callus  is  remarkably  poor  in 
calcium.  Leopold  and  v.  Reuss  found  the  skeletons  of  youthful  parathyroidec- 
tomized rats  poorer  in  calcium  than  those  of  the  control  animals.     To  a  loss. 


196  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

of  calcium  in  the  parathyroid  insufficiency  points  also  the  finding  of  Schiiller 
that  the  bones  in  chronic  tetany  show  in  the  Rontgen  picture  a  characteristic 
rarefaction  of  the  trabeculas  and  marked  atrophy,  an  observation  that  we 
could  confirm  in  almost  all  the  cases,  in  which  we  paid  attention  to  it.  We 
found  this,  however,  in  cases  that  had  never  had  tetany. 

Summarizing  that  which  has  been  said  as  to  the  metabolism,  we  find  that 
in  the  acute  stage  of  tetany  there  exists  an  appreciable  increase  of  the  metabolism, 
that  is  related  to  very  many  factors  of  the  same.  As  most  probable,  we  may  sup- 
pose that  only  in  experimental,  but  also  in  human,  tetany  there  exists  an 
increased  breaking  down  of  albumin  with  disturbances  in  the  intermediary 
albuminous  decomposition,  increased  exchange  of  carbohydrates,  increased  pro- 
duction of  calories,  and  apparently  also  increased  elimination  of  calcium.  A 
part  of  these  alterations  in  metabolism  may  well  depend  on  increased 
irritability  in  the  vegetative  nervous  system.  We  may  expect  in  the  chronic 
stages  of  tetany  alterations  of  metabolism  that  to-day  we  cannot  well 
define. 

The  trophic  disturbances  in  tetany  affect  epithelial  parts  exclusively, 
the  hairs,  nails,  skin,  enamel,  and  ciliary  epithelium.  In  chronic  tetany  there 
are  frequent  statements  as  to  a  thinned-out  growth  of  hair  {Hoffmann, 
V.  Frankl-Hochwart ,  and  others).  An  acute  exacerbation  may  be  introduced 
with  rapid  falling  out  of  the  hair.  Adler  and  Thaler  in  their  experiments  on 
dogs  found  the  faUing  out  of  hair  a  direct  premonitory  symptom  of  tetany. 

Also  Pfeijfer  and  Meier  observed  in  ectomized  animals  falling  out  of  hair 
as  the  direct  symptom  of  tetany.  Speiglcr  in  a  case  of  chronic  tetany  found 
that  the  thinned-out  and  very  thin  hair  was  split  at  the  point  {trichorrhexis). 
Also  the  nails  frequently  show  trophic  disturbances,  they  become  brittle  and 
there  may  occur  complete  necrosis  that  leads  to  casting  off  of  the  nails;  rapid 
substitution  occurs,  however,  after  subsidence  of  the  acute  stage.  In  a  new 
attack  the  process  may  be  repeated.  An  instructive  case  is  reported  by 
Hojfmann.  It  is  that  of  a  woman  who  had  passed  through  five  normal  de- 
liveries. After  the  fifth  pregnancy,  she  developed  tetany  with  distinct 
edema  of  the  hands.  The  finger  nails  fell  out.  A  year  later  tetany  recurred. 
This  time  the  hair  fell  out.  After  a  year,  new  pregnancy  and  tetany;  after 
the  delivery  again  trophic  alterations  of  the  finger  nails.  After  a  half  year, 
at  the  time  of  a  new  pregnancy,  again  tetany,  with  which  was  associated  loss 
of  nails  and  hair.  In  the  tetany  of  children  loss  of  the  finger-nails  seems 
to  be  very  rare.  Pineles  found  in  the  literature  only  one  observation  by 
Hoffmann,  in  a  three  and  one-half-year-old  child. 

The  skin  of  the  face  and  of  the  extremities  shows  in  acute  cases  a  puffy 
appearance  (angiospasm[?],  see  what  is  stated  previously),  causing  a  character- 
istic expression  of  crying. 

Pigmentations  of  the  skin  are  rare.  Kocher  states  that  after  total  ex- 
cision of  the  thyroid  gland  in  many  individuals  there  occur,  if  the  tetany 


TETANY  197 

symptoms  predominate,  marked  pigmentations  progressing  as  far  as  bronzed 
skin. 

Of  greatest  interest  is  the  formation  of  cataracts.  Already  Meinert  had 
observed  in  tetany  a  case  of  cataract,  and  the  first  exact  investigations  began 
with  Peters.  Important  information  was  furnished  by  Erdheim,  Pineles, 
Zirm,  Sperber,  Bartels,  v.  Frankl-Hochwart,  Schonborn,  and  others.  The 
cataract  of  tetany  i^  characterized  by  its  very  rapid  development.  It  is  not 
at  aU  rare  in  children.  It  is  especially  frequent  in  the  tetany  of  pregnancy, 
and  in  women  between  the  ages  of  eighteen  and  forty  years,  as  observed  by 
Zirm  and  Sperber.  In  youthful  individuals  it  occurs  more  frequently  as  nuclear 
cataract,  in  older  individuals  as  cortical  cataract.  Peters  was  the  first  to 
show  that  the  cataract  formation  was  brought  about  by  degenerative  changes 
in  the  ciliary  epithehum.  This  caused  a  molecular  concentration  of  the 
water  in  the  chamber,  thereby  damaging  the  lens.  Erdheim  produced  tetany 
cataract  by  parathyroidectomy  in  rats.  We  are  indebted  to  Pineles  for  the 
information  that  the  cataract  formation  occurs  in  all  forms  of  tetany. 

Hanke  on  histological  examination  of  the  globe  of  the  forty-nine-year-old 
man  who  sufi"ered  with  chronic  tetany  and  cataract  found  optic  neuritis  and  a 
characteristic  degeneration  of  the  pigment  epithelium  of  the  posterior  sur- 
face of  the  iris,  similar  to  that  observed  in  diabetes  mellitus.  Pineles  had 
already  attached  theoretic  value  to  the  circumstance  that  cataract  formation 
could  occur  in  tetany  as  well  as  in  diabetes. 

Of  recent  date  are  the  investigations  concerning  the  disturbances  in 
tooth  formation.  Erdheim  first  observed  that  there  occurred  in  rats,  one  and 
one-half  to  two  and  one-half  months  after  the  operation,  opaque  spots  on  the 
anterior  surface  of  the  incisor  teeth  which  gradually  advanced  toward  the 
points  with  the  teeth's  growth.  Either  the  tooth  breaks  oft"  at  this  point  or 
the  defect  in  the  enamel  heals,  leaving  behind  a  shallow  groove.  The  tooth 
may  also  break  in  the  alveolus,  in  which  case  suppuration  of  the  latter  occurs. 
Erdheim  observed  a  deficient  calcification  of  the  dentine.  Even  the  short 
cessation  of  parathyroid  function  that  occurs  in  autotransplantation  of  the 
parathyroid  is  sufficient  to  determine  the  appearance  of  stripes  poor  in  cal- 
cium in  the  dentine  of  young  rats.  An  especial  clinical  interest  to  Erdheim' s 
studies  is  given  by  the  investigations  of  Fleischmann.  This  w^orker  held  the 
view  that  the  defect  of  enamel  so  commonly  observed  w^as  due,  not  as  was 
formerly  supposed  to  rachitis,  but  to  tetany.  He  points  to  the  dispropor- 
tion between  the  frequency  of  rachitis  and  hypoplasia  of  the  enamel.  In 
rachitis  are  regularly  found  alterations  in  the  dentine;  in  tetany,  however, 
one  always  finds  hypoplasia  of  the  enamel  leading  to  the  formation  of  hori- 
zontal transverse  surfaces.  When  frequent  exacerbations  of  the  tetany 
have  occurred,  are  found  numerous  furrows  below  one  another.  Fleisch- 
mann investigated  ten  children  who  had  suft'ered  from  tetany  and  found  in 
all  the  above-mentioned  hypoplasia,  and  indeed  this  was  present  only  on 


198 


THE    DISEASES    OF    THE    PARATHYROID    GLANDS 


those  teeth  that  had  been  present  during  the  course  of  the  illness.  Nearly 
all  of  the  children  had  also  had  rachitis.  Fleischmann  points  out,  however, 
that  rachitis  lasts  much  longer  than  tetany,  and  also  attains  its  acme  much 
later.  Fleischmann  also  finds  support  for  his  view  in  the  statement  of 
Fuchs  that  children  with  lamellar  cataract  almost  always  show  hypoplasia 
of  the  enamel.  In  individuals  with  hypoplasia  of  the  enamel,  in  whom 
nothing  is  known  of  their  having  had  tetany,  there  may  have  existed  a 
latent  tetanic  condition  in  early  childhood.  Very  convincing  is  an  obser- 
vation of  Spiegler  in  a  case  of  recurring  tetany,  who  had  an  attack  every 
spring  during  eight  years.  In  this  case  it  was  known  that  the  tetany  had 
first  made  its  appearance  at  the  end  of  the  second  year  of  life.  All  teeth 
whose  crowns  must  have  been  formed  at  this  time  were  normal,  while  the 
teeth  whose  crowns  developed   later  showed  defects  of  the  enamel.     An 


Yic.  29. — Enamel  defect  in  tetany. 

entirely  similar  case  w^as  observed  by  Kahn  and  myself  (Observation  XXIII). 
Here  were  found  on  the  canine  and  incisor  teeth  punctiform  defects  of 
enamel  often  arranged  in  parallel  rows;  the  upper  parts  of  the  molars  were 
partly  broken  off.  The  patient's  mother  stated  definitely  that  already  in 
the  first  year  of  life,  but  more  especially  in  the  second  and  third  years,  he 
had  spasms  of  the  glottis  and  spasms  of  the  hands,  while  a  severe  rachitis 
was  added  to  the  picture  only  in  the  third  year. 

The  above  illustration  (Fig.  29)  shows  the  defects  of  enamel  observed  by 
us  in  another  case. 

The  connection  between  tetany  and  defects  of  the  enamel  is  by  all  this 
evidence  put  on  a  sound  basis;  and  I  shall  not  discuss  the  possibility  of 
these  defects  being  brought  about  by  other  causes. 

Perhaps  the  conjunctivitis  accompanying  tetany  may  also  be  regarded  as 
a  trophic  disturbance.  De  Quervain  observed  that  parathyroidectomized 
dogs  often  suft'er  from  severe  conjunctivitis.     I  saw  this  almost  regularly  in 


TETANY  199 

parathyroidectomized  dogs  and  cats.  In  the  case  previously  mentioned  (Ob- 
servation XXIII)  it  happened  that  the  conjunctivitis  regularly  became 
exacerbated  with  the  aggravation  of  the  tetany. 

Yet  a  few  words  with  regard  to  growth  disturbances  in  tetany.  SchuUer 
investigated  five  cases  of  rachitis  tarda  and  found,  besides  pronounced 
Chvostek's  symptoms,  remaining  behind  in  growth,  delayed  ossification  and 
dentition,  and  marked  atrophy  of  the  bones;  the  last  was  also  found  in  an 
exactly  investigated  case  of  the  chronic  recurring  form  of  tetany,  and  also  in 
three  juvenile  cases  of  occupation  tetany.  On  the  contrary,  a  case  of  tetany 
after  strumectomy,  and  some  cases  of  tetany  of  maternity  showed  normal 
relations.  SchuUer  points  out  that  tetany  may  also  occur  in  combination 
with  osteomalacia,  and  believes  that  tetany  may  induce  rachitic  alterations 
before  the  cessation  of  bone  growth,  and  osteomalacia  after  it.  A  similar 
view  is  held  by  ErdJieim  on  the  basis  of  histological  examination  of  the 
skeleton,  and  especially  of  callus  formation  in  rats  after  parathyroidectomy. 
Kassowitz  had  before  this  supposed  a  casual  connection  between  rachitis 
and  tetany. 

This  view  I  would  not  subscribe  to.  It  is  to  be  expected  that  high-grade, 
and  especially,  long-continued,  absence  of  parathyroid  function  in  youthful 
life  would  lead  to  disturbances  in  growth  of  bones.  We  also  saw  certain  cases 
of  chronic  recurring  tetany,  in  which  the  individuals  were  remarkably  small 
and  showed  retarded  epiphysial  closure.  The  disturbance  has  certainly 
nothing  to  do  with  true  rachitis.  Sometimes,  indeed,  it  is  difficult  to  separate 
the  two  conditions,  as  combinations  of  rachitis  and  tetany  are  extremely 
frequent,  and  according  to  Escherich,  not  less  than  80-90  per  cent,  of  all 
tetany  in  children  is  associated  with  rachitis.  There  are  certainly,  however, 
cases  of  tetany  without  rachitis,  and  cases  of  rachitis  with  tetany  constitute 
only  an  extremely  small  percentage  of  the  whole  number  of  cases.  Also 
the  rarefaction  of  the  bone  trabeculae  described  by  SchuUer  is  not  charac- 
teristic for  a  withstood  tetany,  for  we  have  found  them  in  individuals  who 
have  not  had  tetany.  Experimental  experiences  speak,  too,  against  a  direct 
connection  between  rachitis  and  tetany.  Iselin  observed  remaining  behind 
in  growth  in  parathyroidectomized  rats;  and  similar  observations  have  been 
made  by  Jeandelize,  Moussu,  and  Vassals  and  Generali  on  other  species  of 
animals.  Iselin' s  animals  remained  well  proportioned,  however,  and  showed 
no  bone  perversions. 

I  decline  to  subscribe  to  the  doctrine  of  a  connection  between  tetany 
and  osteomalacia.  The  number  of  cases  in  which  the  diseases  coexisted  is 
not  large.  Blaziceck,  Weber,  E.  Freund,  Schultze,  Becker,  have  reported  such 
cases.  An  exception  in  this  respect  is  only  the  markworthy  observation  of 
Krajewska  from  Bosnia;  she  found  tetany  present  among  one  hundred  fifty 
cases  of  osteomalacia  no  fewer  than  forty-eight  times.  All  forty-eight  cases 
affected  puerperal  women. 


200  THE    DISEASES    OF    THE    PARATHYROID    GLAXDS 

H  ence  there  may  be  regarded  as  the  symptom  belonging  to  chronic 
tetany  at  most  the  rarefaction  of  the  bone  trabeculae  and  the  atrophy.  It 
is  shown  by  the  statistics  of  late  years  that  a  chronic  tetany  existing  from 
earliest  youth  may  damage  the  development  of  the  entire  body.  Disturb- 
an  ces  of  the  development  of  speech  and  of  the  intelligence  are  especially 
frequent  (see  prognosis).  The  development  of  the  sexual  glands  does  not 
appear  to  suffer;  in  isolated  cases  we  can  find  at  least  no  remaining  behind 
in  sexual  development  although  tetany  spasms  may  have  existed  for  years, 
from    early  youth  or  from  just  at  the  time  of  puberty. 

The  symptomatology  of  tetany  would  be  incomplete  were  I  to  neglect 
to  mention  a  series  of  symptoms  that  depend  on  a  functional  disturbance  oj 
other  ductless  glands,  but  are  very  frequently  combined  with  tetany. 

As  has  already  been  mentioned,  Kocher  states  that  after  total  extirpation 
of  the  thyroid  in  human  beings,  there  occur  in  individuals  in  whom  the  symp- 
toms of  tetany  predominate,  marked  pigmentations  progressing  as  far  as 
bronzed  skin.  Probably  in  such  chronic  cachectic  conditions  there  is  a  re- 
d  uction  in  the  activity  of  the  chromaffin  tissue.  Oftenest  occur  symptoms 
that  depend  on  an  alteration  of  thyroid  function.  Not  so  very  rare  in  chronic 
tetany  are  symptoms  of  myxedema,  v.  Frankl-Hochwart,  in  looking  over  his 
cases,  found  symptoms  of  myxedema  as  many  as  thirteen  times  among 
twenty-six  cases.  We  saw  this  alteration  once.  These  myxedematous 
alterations  of  the  skin  occurring  in  chronic  tetany  should  not  be  confused 
with  the  puffiness  of  the  face  previously  described,  or  with  the  edema  of  the 
backs  of  the  hands  that  occurs  in  the  acute  stage,  which  phenomena  are 
properly  regarded  as  angiospastic. 

Kahn  and  /  have  reported  an  observation,  which  in  the  clinical  sense  is 
not  of  less  significance.  In  a  series  of  our  own  cases  we  saw  develop  in  the 
acute  stage  or  immediately  at  its  close  a  slight  hyperthyrosis.  This  con- 
sisted especially  in  tachycardia,  headache,  slight  rise  of  temperature,  increase 
in  blood-pressure,  sweats,  slight  tremor,  and  slight  dift'use  enlargement  of 
the  thyroid.  The  connection  between  our  observations  and  those  of  Frankl- 
Hoch-wart  is  perhaps  this:  that  in  many  cases  of  tetany  at  the  conclusion  of  the 
acute  stage  or  during  an  acute  exacerbation  there  occurs  an  increase  of 
thyroid  activity  and  even  an  appreciable  enlargement  of  the  thyroid  gland, 
which  is  succeeded,  in  the  stage  of  chronic  tetany,  by  a  sHght  degree  of  thyroid 
insufficiency  (see  the  section  on  the  idiopathic  form  of  tetany). 

Pathogenesis  of  Tetany 

It  seems  to  me  suitable  first  to  set  forth  in  detail  the  pathogenesis  of 
parathyroprivic  tetany;  and  then  later  in  the  exposition  of  the  individual 
forms  of  tetany,  to  speak  of  their  etiology  separately. 

As  I  have  already  mentioned  at  the  beginning,  to-day  we  may  regard 


PATHOGENESIS    OF    TETANY  20I 

as  established  that  experimental  tetany  depends  on  the  loss  or  marked 
damaging  of  the  parathyroid  glands.  This  holds  good  for  all  species  of 
animals.  The  course  of  tetany  in  different  animals  is,  however,  different. 
In  some  after  total  extirpation  of  all  the  parathyroids  there  occurs  an  acute 
tetany,  which  after  a  short  time  leads  to  death.  In  others,  for  instance  in 
monkeys,  the  course  is  chronic.  Does  the  complete  loss  of  parath3Toid 
glands  lead  to  tetany  always? 

Here  should  be  mentioned  that  all  authors  are  agreed  that  older  animals 
resist  the  operative  attack  more  readily  than  young  ones.  Important  in 
this  respect  are  the  investigations  of  Iselin,  who  found  that  the  young  of 
partially  parathyroidectomized  rats  are  especially  sensitive  to  the  extirpa- 
tion of  the  parathyroids,  and  die  in  a  few  hours  with  fulminating  epilepti- 
form seizures.  ^Moreover,  there  are  numerous  statements  that  the  simul- 
taneous extirpation  of  thyroid  gland  and  parathyroids  is  better  borne  than 
isolated  parathyroidectomy.  Many  hypotheses  have  been  advanced  to 
explain  this  fact,  a  fact  that  our  own  investigations  fully  substantiate.  The 
most  natural  of  these  seems  to  me  to  be  the  conception  that  on  the  simul- 
taneous extirpation  of  the  thyroid  glands  the  metabolism  and  with  it  the  ex- 
citabihty  of  the  entire  nervous  system  is  reduced,  and  the  function  of  the 
parathyroid  glands  is  then  reduced  in  its  action.  On  the  other  hand,  we 
know  that  procedures  of  the  most  diverse  kinds  and  conditions  that  make 
great  demands  on  the  nervous  system  accelerate  the  outbreak  of  tetany  or 
allow  latent  forms  to  pass  over  into  the  acute  forms.  If  we  here  recog- 
nize too  that  the  influences  that  may  modify  the  course  and  acuity  of  the 
process  may  be  manifold,  we  may  well  assume  that  the  complete  loss  of  all 
parathyroids  leads  to  death  in  all  species  of  animals,  under  the  manifesta- 
tions of  an  acute  or  more  chronic  tetany,  hence  that  the  loss  of  the  para- 
thyroid function  is  incompatible  with  the  long  continuation  of  life.  I  would 
not  off-hand  rehnquish  this  assumption  on  account  of  the  quite  isolated 
contrary  statements.  Haberfeld  and  Schilder  state  that  rabbits  in  which  at 
first  the  four  parathyroids  are  removed,  and  later  the  thymus  gland  ^dth 
the  accessory  thyroid,  continue  to  live.  Continuous  serial  sections  show 
the  absence  of  any  parathyroid  tissue.  Wiener  even  asserts  that  of  forty-five 
parathyroidectomized  animals,  20  per  cent,  did  not  show  any  manifestations 
of  tetany.  In  my  own  numerous  experiments  on  dogs,  cats  and  rabbits,  I 
have  never  seen  an  animal  survive.  The  unconditional  importance  of  the 
function  of  parathyroids  for  life  is  also  held  by  Biedl,  Hagenbach,  and 
others.  As  long,  therefore,  as  no  further  statements  as  to  this  question 
exist,  I  would  still  beheve  that  in  the  experiments  of  Haberfeld  and  Schilder 
and  Wiener  that  have  been  mentioned,  accessory  thyroids  may  have  escaped 
demonstration. 

As  regards  the  mechanism  of  parathyroid  function,  numerous  opin- 
ions have  been  promulgated.     In  the  foreground  stands  the  views  as  to 


202  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

the  cletoxicating  function.  The  parathyroids  would  seem  to  furnish  to  the 
blood-path  a  hormone  which  renders  innocuous  poisons  that  exist  in  the 
body.  Originally  the  thyroid  gland  was  looked  upon  as  the  organ  preparing 
the  poison  (Vassale  and  Generali).  'Ldit^Xy  Pineles,  Pfeijfer  and  Meyer,  Oni 
and  Beste.  Berkeley  and  Beebe,  and  most  recently,  especially  Wiener,  have 
turned  attention  from  the  thyroid  and  have  assumed  that  in  the  bodies  of 
animals  with  tetany  there  circulates  a  specific  poison  or  one  originating  other- 
wise in  metabolic  processes. 

It  is  impossible  for  me  to  enter  intimately  into  the  numerous  experiments 
that  have  been  instituted  for  the  establishment  of  the  hypothesis.  I  would 
mention  only  the  most  important.  Pfeijfer  and  Meyer  state  that  in  the  sera 
collected  in  the  death  agony,  of  seventeen  dogs  affected  with  tetany,  they  have 
found  in  six  a  toxic  principle  which  injured  partially  parathyroidectomized 
mice,  while  the  sera  of  normal  dogs  were  inactive.  The  fact  that  animals  with 
tetany  are  very  sensitive  to  the  various  procedures  tends  to  make  one  sceptical 
as  to  the  value  of  these  experiments.  Ceni  and  Besta  have  tried  to  obtain 
an  immune  serum,  injecting  the  serum  of  totally  ectomized  dogs  into  rabbits 
and  goats,  and  reinjecting  the  sera  of  these  into  the  tetanic  dogs.  Almost 
regularly  they  cured  the  acute  manifestations,  although  none  of  the  animals 
remained  alive.  H.  Wiener  followed  a  similar  course  for  experimentation, 
except  that  he  used  cats  both  for  immunization  and  for  treatment.  In  some 
animals  (not  all)  he  succeeded  in  combating  the  tetanc  symptoms  per- 
manently. The  residual  thyroid  glands  of  these  animals  were  examined  and 
found  to  contain  no  piece  of  parathyroid  tissue.  The  assumption  of  Wiener 
that  in  cats  there  are  no  accessory  parathyroids  must,  in  consideration  of  the 
importance  of  such  experiments,  first  be  shown  by  painstaking  investigations. 
The  doubt  is  increased  by  the  statement  of  Wiener  that  in  some  experiments 
also  the  injection  of  entirely  normal  serum  permanently  set  aside  the  tetanic 
symptoms. 

Although,  up  to  the  present,  the  detoxication  theory  of  tetany  cannot  be 
refuted,  it  does  not  seem  to  me  to  have  been  satisfactory.  The  assumption 
of  a  detoxicating  function  has,  up  to  the  present,  played  a  great  role  in  the 
pathology  of  all  the  ductless  glands.  However,  it  seems  to  me  that  up  to  the 
present  there  does  not  exist  a  single  fact  that  strictly  demonstrates  this 
supposition.  As  with  the  other  ductless  glands,  so  with  the  parathyroids, 
another  supposition  seems  plausible,  a  supposition  that  was  first  suggested 
by  Rudinger  and  myself  and  then  further  developed,  with  modifications,  by 
Kahn  and  myself. 

The  cardinal  symptoms  of  tetany  depend  on  increased  excitability  or 
abnormal  conditions  of  irritability  of  the  nervous  system.  As  to  the  seat 
of  the  abnormal  irritability  we  may  say  the  following:  ScJiiff  had  already 
shown  that  in  tetany  tremors  and  spasms  ceased  after  the  section  of  the 
peripheral  nerves.     Rudinger  and  /  have  repeated  these  experiments,  and 


PATHOGENESIS    OF    TETANY  203 

have  modified  them  in  various  ways.  When  we  had  extirpated  the  para- 
thyroids in  cats  and  at  the  same  time  had  cut  the  sciatic  nerve,  immediately 
below  its  exit  from  the  pelvis,  no  hyperexcitability  made  its  appearance  in  the 
nerve  peripherally  from  the  site  of  the  section;  much  more  did  the  nerve 
gradually  become  excitable  to  the  galvanic  current  in  about  the  same  time  as 
after  the  section  in  normal  animals.-^  If,  however,  we  first  obtain  our  tetany 
through  parathyroidectomy  and  then  transect  the  nerve  when  it  had  already 
become  hyperexcitable,  we  find  that  the  hyperexcitabihty  continues  for  some 
time,  and  then  only  gradually  passes  through  a  period  of  normal  irritability 
(with  normal  electrical  reaction)  into  the  condition  of  nonexcitability.  In 
some  experiments  it  takes  nine  days  before  this  condition  is  reached.  From 
this,  in  reliance  on  former  experiments  of  Frdhlich  and  Lowi  on  nerve-muscle 
preparations  of  the  octopod  Eledona  moschata,  we  have  concluded  that 
under  normal  circumstances  the  nerve  is  supplied  [loaded,  stored,  ausladen] 
from  its  trophic  center,  the  ganglion-cell,  with  an  as  yet  unknown,  indefinite 
substance,  and  that  separation  from  this  center  is  followed  by  a  gradual  loss 
of  this  supply  and  by  degeneration,  and  that  in  tetany  there  exists  an  ab- 
normally high  loading  of  the  ganglion-cell  or  of  whole  neuron  proceeding  from 
it.  Biedl  had  set  forward  to  this  experiment  the  objection  that  pressure  on 
the  nerve  below  the  point  of  severance  can  no  longer  elicit  muscular  spasm. 
According  to  Schlesinger's  explanation  of  Trousseau's  phenomenon,  however 
(reflex-process  on  account  of  irritation  of  sensory  nerves),  nothing  else  than 
this  is  to  be  expected.  That,  moreover,  no  muscular  spasm  appears  any 
longer  in  the  extremity  in  question  is  not  remarkable,  as  every  new  impulse 
from  the  ganglion-cell,  which  is  always  storing  anew,  is  lacking. 

Further  investigations  have  shown,  moreover,  that  an  association  of 
the  ganglion-cells  of  the  spinal  cord  with  higher  centers  is  not  necessary  to 
render  possible  in  tetany  or  to  obtain  in  it  the  abnormal  loading  of  the 
ganglion-cells.  Already  Munk  had  stated  that  after  transection  of  the 
spinal  cord  the  spasms  in  the  paralyzed  hind-extremity  persisted,  and 
Horsley  and  Lanz  have  since  ascertained  that  after  extirpation  of  the  cortical 
motor  areas  on  one  side,  the  tetany  may  persist  on  the  other  half  of  the  body. 

Our  own  investigations  showed  that  after  section  of  the  spinal  cord  in 
animals  suffering  with  tetany  the  hyperexcitability  in  the  paralyzed  hind- 
extremities  remained  exactly  as  in  the  fore-extremities  until  death.  BiedVs 
statement  that  there  appeared  in  the  paralyzed  extremities  lightning-like 
contractions  and  fibrillary  muscular  twitchings,  but  that  all  traces  of  a  toxic 
rigidity  were  absent,  are  in  direct  contradiction  to  Munk's  statement  and 
our  own.     In  addition  we  could  most  definitely  assure  ourselves  that  we 

^  In  more  recent  investigations  MacCallum  (Journal  of  the  American  Medical  Association,  19, 
191 2,  p.  319)  found  that  the  peripheral  part  of  the  nerve  also  becomes  hyperexcitable,  if  it  had 
been  cut  off  before  the  parathyroid  had  been  excised.  I  cannot  state  off-hand  the  explanation 
for  the  divergence  of  our  observations. 


204  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

saw  in  the  paralyzed  extremities,  in  certain  cases,  in  cats  and  dogs,  after 
complete  section  of  the  spinal  cord,  the  occurrence  of  most  intense  spasms 
in  the  paralyzed  extremities  in  the  acute  attack.  Moreover,  the  occurrence 
of  such  spasms  was  not  at  all  necessary.  The  exact  demonstration  of  the 
galvanic  hyperexcitability  of  the  nerves  of  the  posterior  extremities,  which 
develop  even  when  the  transection  of  the  spinal  cord  has  been  done  at  the 
same  time  with  the  extirpation  of  the  parathyroids,  shows  with  certainty 
that  the  cause  of  the  tetanic  changes  lies  in  the  ganglion-cells  of  the  spinal  cord, 
and  not,  as  MacCalluni  and  Biedl  believe,  in  the  higher  centers.  By  this  we  do 
not  mean  to  assert  that  in  tetany  the  higher  centers  do  not  likewise  share  in 
the  condition  of  hyperexcitability,  and  that  the  course  of  the  twitchings  in 
the  tetanic  attack  may  not  under  circumstances  be  concomitantly  influenced 
by  the  centers  that  lie  higher. 

Just  as  the  motor  nerves  maintain  their  hyperexcitability,  we  may 
assume  that  the  same  is  true  of  the  sensory  and  vegetative  nerves.  It 
is  very  probable  that  the  neurons  of  different  orders  become  involved  in  a 
definite  sequence.  In  the  slight  grades  of  human  tetany  it  is  especially  the 
neurons  of  the  first  order  that  are  affected.  Here  the  occurrence  of,  as  a  rule, 
bilateral  spasms,  convulsions,  and  pains,  points  to  the  spinal  cord  or  to  the 
medulla  oblongata  as  the  seat  of  the  affection.  In  the  acute  stage  the  vege- 
tative nervous  system  is  also  affected  concomitantly.  In  the  severe  cases 
phenomena  tend  to  occur  that  point  to  involvement  of  still  higher  centers. 
Forced  movements  point  to  the  mid-brain,  disturbances  of  equilibrium  to 
the  cerebellum,  epileptiform  convulsions  to  participation  of  the  motor 
cortical  areas,  and  psychoses  that  of  the  cortex  in  general.  A  similar  train 
of  thought  was  followed  by  de  Qnervain  in  1893,  and  later  by  Ast,  and  others. 
In  children  we  actually  find  a  mounting  from  cord  to  cerebrum,  with  in- 
creasing intensity.  Here,  as  Escherich  emphasizes,  the  higher  centers  are 
more  frequently  and  more  strongly  involved.  The  retrogression  of  the 
condition  tends  to  follow  a  reversed  series  of  involvements. 

Here  I  quote  verbatim  the  conclusions  arrived  at  in  the  work  of  Kahn 
and  myself.  "In  tetany  there  exists  an  abnormal  irritability  of  the  motor, 
sensory,  special  sensory,  and  vegetative  ganglion-cells  that  from  here  as  a 
starting-point  involves  the  entire  neuron.  It  is  principally  the  peripheral 
neurons  that  are  found  in  this  state  of  hyperirritability.  Neurons  of  higher 
orders  may,  however,  be  concomitantly  involved.  This  abnormal  state 
expresses  itself  chiefly  in  a  heightened  excitability  to  mechanical,  electrical, 
or  chemical  irritants  (latent  tetany).  Nevertheless  the  abnormal  tension 
in  the  gariglion-cell,  either  per  se  or  through  any  other  occasioning  factor, 
may  lead  to  a  heightened  irritability  in  the  organs  supplied  by  it,  and  may 
become  manifest  in  tonic  spasms  and  fibrillary  twitchings  of  the  trans- 
versely striated  muscles,  in  paresthesias,  in  tonic  contractures  of  the  smooth 
muscles,  in  heightened  secretional  processes,  etc. 


PATHOGENESIS    OF    TETANY  205 

"Thereby  is  found  a  partial  unloading  of  the  ganghon-cells,  although 
apparently  not  in  very  great  degree,  so  that  the  hyperexcitability  is  still 
present  after  the  attack.  This  conception  explains  why  at  one  time  an 
occasioning  factor  may  call  forth  a  spasm,  while  a  short  time  afterward  it 
is  inactive,  perhaps  becoming  active  again  on  the  next  day,  and  why  the 
spontaneous  condition  of  hyperirritability  in  tetanies  is  subject  to  such 
significant  rapid  change.  This  behavior  may  be  observed  especially  beauti- 
fully on  animals  that  have  been  parathyroidectomized;  these  dogs  and  cats 
may  be  the  victims  of  the  most  severe  spasms,  and  yet  a  few  hours  later  may 
play  as  vivaciously  as  ever.  Only  the  exact  investigation  of  the  electrical 
and  mechanical  hyperexcitability  now  affords  knowledge  as  to  the  latent 
tetanic  condition.  This  view  also  makes  appear  intelligible  the  fact  that 
certain  nerve  territories  that  have  immediately  met  with  numerous  irrita- 
tions (peripheral  neurons)  are  especially  preferred,  and  that  the  conditions 
of  irritability  in  the  different  nerve  territories  are  of  different  strengths,  and 
may  be  subject  to  considerable  change. 

"In  what  relation  do  the  parathyroids  stand  to  the  hyperexcitability 
or  to  the  condition  of  excitability  of  the  ganglion-cells?  'Everywhere  where 
excitation  is,  is  also  present  inhibition'  (Meltzer).  According  to  Bechterew, 
the  inhibitory  processes  are  to  be  regarded  as  an  indispensable  protective 
arrangement  of  the  central  nervous  system.  The  normal  condition  of 
irritability  of  the  ganglion-cells  is  guaranteed  only  by  the  finest  regulation  of 
increase  of  activity  [Forderung]  and  inhibition.  Falta  and  Rudinger  have 
expressed  the  opinion  that  the  parathyroid  glands  exercise  inhibitory  influences 
on  the  ganglia  by  a  hormone,  and  that  the  diminution  or  complete  with- 
drawal of  this  inhibition  leads  to  an  abnormal  loading  of  the  cell  with  energy. 

"We  do  not  know  anything  more  intimately  as  to  the  action  of  this 
hormone.  It  is  not  impossible,  however,  to  bring  this  hypothesis  into  com- 
bination with  that  developed  by  MacCalluvi  and  Vogtlin,  by  our  following 
the  assumption  of  these  authors  that  the  parathyroid  glands  influence  the 
calcium  metabolism  in  the  central  nervous  system  by  means  of  a  hormone. 
The  hormone  of  the  parathyroid  glands  might  thus  be  regarded  as  an  as- 
similatory  hormone,  with  the  withdrawal  of  which  there  occurs  loss  of  cal- 
cium in  the  ganglion-cells  and  hyperirritabihty  of  these." 

The  details  up  to  the  present  confine  themselves  to  the  mechanism  by 
which  insufficiency  of  the  parathyroids  leads  to  tetany;  they  set  forth  that 
all  forms  of  tetany  depend  on  an  absolute,  or  at  least,  a  relative  insufficiency 
of  the  parathyroids.  The  dift'erent  causes  of  parathyroid  insuf&ciency 
will  be  discussed  later,  with  the  exposition  of  the  different  forms  of  tetany 
and  the  pathological  anatomy. 

We  shall  add  a  few  words  as  to  the  relation  of  myotonia,  epilepsy  and 
eclampsia  to  tetany.  The  occurrence  in  tetany  of  symptoms  similar  to 
those  of  myotonia  is,  as  already  mentioned,  not  rare.     The  fact  that  they 


206  THE    DISEASES    OF    THE    PARATHYROK)    GLANDS 

are  also  observed  in  experimental  tetany,  ensures  relationship  to  tetany. 
The  intention  spasms  may  be  explained  by  the  fact  that  the  will  impulse 
furnishes  the  determining  factor  for  a  tetany  spasm.  In  addition  there 
often  occurs,  however,  pitting  on  percussion  and  the  myotonic  electrical  reac- 
tion. On  the  other  hand  there  occur  true  cases  of  myotonia  congenita  to 
which  are  superadded  the  clinical  picture  of  tetany. 

In  these  cases,  as  v.  Orzechowski  points  out.  the  symptoms  of  tetany  are 
only  of  a  shght  grade;  with  the  decline  of  the  tetany,  the  myotonia  remains. 
This  coincidence  of  tetany  and  myotonia  has  been  sufficient  for  Lundhurg 
and  others  to  ascribe  the  cause  of  myotonia  to  an  insufficiency  of  the  para- 
thyroids. The  assumption  seems  to  me  to  be  fully  unsubstantiated,  as  in 
true  myotonia  all  symptoms,  that  according  to  experimental  experiences  we 
have  come  to  regard  as  the  cardinal  symptoms  of  parathyroid  insufficiency, 
are  absent.  Myotonia  is  an  affection  of  the  muscles  (Erh,  Schulize  and 
Schiefendecker  and  others).  The  occurrence  of  symptoms  similar  to  those 
of  myotonia  in  tetany  perhaps  finds  its  explanation  in  a  definite  alteration  of 
the  metabolism.  It  is  remarkable  that  just  those  animals  in  whom  the  thy- 
roids and  parathyroids  have  been  removed  show  these  manifestations. 
Furthermore,  there  is  a  case  of  Hof  mannas  in  whom  the  myotonic  symp- 
toms disappeared  on  the  administration  of  thyroid  gland,  and  in  whom  they 
reappeared  after  withdrawal  of  the  treatment,  while  the  tetanic  symptoms 
were  not  essentially  aft'ected.  Perhaps  there  is  a  certain  relation  between 
myotonia  and  the  high-grade  mechanical  hyperexcitability  of  the  muscles 
such  as  is  not  rarely  seen  in  cachectic  conditions. 

As  for  epilepsy,  we  have  already  mentioned  in  the  consideration  of  the 
symptomatology  that  tetany  may  develop  on  an  epilepsy  that  has  lasted  for 
a  long  time,  and  that  tetany  and  epilepsy  may  develop  simultaneously  in 
individuals  not  previously  epileptic,  and  indeed  may  improve  simultaneously. 
In  many  cases  the  epileptic  convulsions  occurring  in  severe  tetanic  at- 
tacks may  remain  the  sole  manifestation  of  epilepsy.  It  should  fur- 
ther be  mentioned  that  Chvostek's  phenomenon  is  not  rarely  elicitable 
in  epileptics,  and  that  Fleischniann  and  Poetzl  as  reported  by  Redlich  found 
twenty-eight  times  defects  of  the  enamel  among  sixty  epileptics,  a  fact 
that  perhaps  indicates  that  individuals  who  in  early  years  have  passed 
through  tetany,  later  often  become  epileptics.  Most  important  for  the 
relationship  between  tetany  and  epilepsy  are  the  cases  of  parathyroprivic 
tetany  with  epilepsy.  Redlich  has  collected  twenty  such  cases  from  the 
literature  and  adds  a  case  of  his  own.  The  frequent  coincidence  of  tetany 
and  epilepsy  shows  that  this  combination  is  "no  accidental  happening'' 
(zj.  Frankl-Hochwart,  Schulize,  Redlich).  As  to  the  intimate  connection 
we  really  know  nothing  certain.  Westphal  supposed  that  tetany  and 
epilepsy  depended  on  the  same  toxic  cause,  which,  as  Chvostek  later  elabo- 
rated, led  both  to  alterations  in  the  central  nervous  system  and  to  func- 


PARATHYROPRIVIC    OR    TRAUMATIC    TETANY  207 

tional  disturbances  of  the  epithelial  bodies.  Pineles  supposed  that  the 
toxin  of  tetany  produced  a  latent  predisposition  to  epilepsy;  Curschmann  that 
it  increased  the  excitability  of  the  cortex  and  subcortex.  Experimental 
pathology  has  as  yet  furnished  no  reliable  evidence.  In  a  cat  in  which  Kreidl 
extirpated  three  parathyroids,  epileptic  attacks  regularly  followed  operations 
on  different  parts  of  the  cortex.  Redlich  could  not  confirm  the  results  of 
this  experiment  when  he  repeated  it.  Only  in  one  experiment,  an  opera- 
tion on  the  brain  cortex  after  total  thyroparathyroidectomy,  did  he  notice 
the  simultaneous  occurrence  of  severe  tetanic  and  severe  epileptic  attacks. 

Attempts  have  also  been  made  to  refer  epilepsy  without  tetany  to  an 
insufficiency  of  the  parathyroids.  As  was  to  have  been  expected,  pathological 
anatomy  did  not  substantiate  this  hypothesis.  Erdheim  examined  the 
parathyroid  glands  in  two  cases  of  status  epilepticus;  in  one  they  were  en- 
tirely normal  and  in  the  other  they  were  shghtly  sclerotic.  Claude  and 
Schmiergeld  found  no  constant  change  of  tissue  in  thirteen  cases. 

The  relationship  of  tetany  to  eclampsia  has  not  yet  been  cleared  up  in  a 
satisfactory  manner.  In  the  years  of  childhood  tetany  may  occur  under 
the  guise  of  eclamptic  attacks,  as  has  been  mentioned  already.  It  has  been 
held  that  children  who  have  suffered  wdth  eclampsia,  later  became  epi- 
leptic. Birk  could  not  find  this  in  his  material,  to  which  are  opposed  the 
statements  of  Potpetschnigg.  The  eclampsia  of  adults  is  as  a  rule  to  be 
separated  from  tetany;  for  in  eclampsia  the  cardinal  symptom  of  parathy- 
roid insufficiency,  the  galvanic  excitability,  is  absent.  Erdheim  could  not  cor- 
roborate the  statements  of  Pepere  and  Zanfrognini,  who  found  a  lessened 
number  of  parathyroid  glands  in  their  cases  of  eclampsia.  In  four  cases 
of  eclampsia  examined  by  Erdheim  the  parathyroids  were  normal,  except 
for  the  fact  that  they  were  very  hyperemic  and  were  permeated  with  small 
hemorrhages,  which  manifestations  are  certainly  to  be  regarded  as  secondary. 

FORMS  OF  TETANY  AND  PATHOLOGICAL  ANATOMY 

I.  The  Parathyroprivic  or  Traumatic  Tetany 

It  was  first  noticed  by  Nathan  Weiss  that  in  Billroth'' s  clinic  the  extirpation 
of  the  thyroid  gland  was  often  followed  by  tetany.  Since  that  time  the 
literature  as  to  this  subject  has  growm  enormously.  The  question  is  handled 
with  especial  thoroughness  in  the  publications  of  v.  Eiselsherg  and  Koclwr. 
V.  Eiselsherg  in  his  "  Diseases  of  the  Thyroid  Gland"  pubHshes  a  classic 
description  of  tetany  after  extirpation  of  the  thyroid  gland.  In  Vienna  tetania 
"  strumipriva "  was  observed  much  more  frequently  than  in  Bern.  Among 
forty  cases  of  total  extirpation  of  the  thyroid  gland,  tetany  was  seen  hjKocher 
only  nine  times,  of  which  number  only  three  were  pronounced  cases;  among 
thirty  cases  of  partial  extirpation  only  six  were  acute  tetany;  among  ninety- 


208  THE    DISEASES    OF    THE    PAR.\THYROID    GLAXDS 

seven  operations  in  Basedow's  disease,  only  five  were  tetany;  one  case  of  liga- 
tion of  all  four  arteries  supplying  the  thyroid  gland  led  to  peracute  tetany. 
Epileptiform  tetany  has  been  observed  by  v.  Eiselsberg,  Kocher,  and  others,  in 
the  wake  of  partial  extirpation.  Originally  tetany  was  attributed  to  the  fail- 
ure of  the  thyroid  gland.  With  the  awakening  knowledge  of  the  significance 
of  the  parathyroid  function  were  heard  loud  voices  referring  thyroid-gland 
tetany  to  the  simultaneous  damaging  or  removal  of  the  parathyroids. 
Fundamental  for  this  view  are  the  investigations  of  Pineles,  and  of  Erdheim. 
The  latter  observed  three  cases  that  had  died  of  more  or  less  acute  tetany 
after  strumectomy.  In  the  first  case,  which  had  shown  a  more  chronic 
course,  the  entire  throat  portion  was  cut  in  the  serial  sections;  it  was  found 
that  all  four  parathyroids  were  missing,  although  two  small  accessory  para- 
thyroids were  found  in  the  midst  of  the  thymus  tissue.  In  both  the  other 
cases,  which  had  pursued  a  more  acute  course,  parathyroids  capable  of  func- 
tionating were  not  to  be  found.  Erdheim  pointed  out  that  the  great  fre- 
quency of  strumiprivic  tetany  in  Vienna  had  its  explanation  in  the  fact  that 
there  the  operations  on  the  thyroid  gland  were  conducted  according  to  the 
old  methods,  while  Mikulicz's  wedge  resection  or  Kocher' s  resection  enuclea- 
tion are  rather  adapted  to  avoid  the  parathyroids.  However,  the  genius 
loci  must  not  be  entirely  overlooked  in  the  explanation  of  the  fact. 

To-day,  when  we  are  well  informed  as  to  the  significance  and  topography 
of  the  parathyroids,  tetany  after  operations  belongs  to  the  greatest  of  rarities. 
A  preparatory  search  for  the  parathyroids  is  not  necessary;  sufficient  is 
adherence  to  the  propositions  of  Pineles  and  Erdheim  to  let  remain  both  the 
lower  lobes;  search  for  the  parathyroids  is  directly  indicated  only  when  in 
malignant  struma,  it  becomes  necessary  to  remove  the  entire  thyroid  gland, 
V.  Eiselsberg  has  reported  a  case  in  which  the  greater  part  of  the  thyroid 
gland  was  removed  for  malignant  adenoma.  Myxedema  developed,  and 
retrogressed  after  the  appearance  of  metastases  in  the  sternum.  Ex- 
tirpation of  these  metastases  (healing  by  secondary  intention)  was  fol- 
lowed by  a  recurrence  of  the  myxedematous  symptoms  and  by  tetany. 
Erdheim  explains  this  case  by  the  fact  that  at  the  first  operation  there  was 
left  behind  one  of  the  lower  chief  parathyroids,  and  that  this  became  sac- 
rificed at  the  second  operation. 

The  etiology  of  the  thyroprivic  tetany  is  thus  clear.  This  form  of  tetany 
depends  on  the  loss  or  the  damaging  of  the  parathyroids  at  the  operation. 

Proescher  and  Diller  report  a  case  of  traumatic  tetany  in  the  adult.  A 
young  man  developed  typical  tetany  eight  days  after  a  severe  blow.  At 
autopsy  there  were  found  numerous  small  fresh  hemorrhages  in  parathyroids, 
which  were  in  addition  h}TDoplastic.  Belonging  to  traumatic  tetany  are  also 
numerous  cases  of  the  tetany  of  sucklings,  as  we  shall  see  later  in  the  section 
on  tetanv  in  children. 


TETANY  IN   INFECTIOUS   DISEASES   AND   INTOXICATIONS  209 

2.  Tetany  in  Diseases  of  the  Thyroid  Gland 

Cases  of  tetany  in  myxedema  are  rare.  They  are  strikingly  frequent, 
combined  with  epilepsy  (cases  of  Stewart,  Schdnhorn,  and  myself). 

Cases  of  thyroiditis  with  tetany  were  observed  by  v.  Eiselsberg,  and 
Kocher.  Although  there  are  no  pathologico-anatomical  investigations, 
yet  it  may  readily  be  supposed  that  acute  inflammatory  or  sclerosing  proc- 
esses that  attack  the  thyroid  also  involve  the  parathyroid  in  sympathy.  In 
strumous  degeneration  of  the  thyroid  gland  the  parathyroids  associated 
with  the  capsule  may  become  involved  and  thus  are  brought  to  atrophy. 
Such  cases  have  been  reported  by  Steinlechner,  Fraisseix,  Hirschl,  Marinesco, 
Jacobi,  and  others.  I  shall  speak  in  the  consideration  of  idiopathic  tetany 
of  the  triad  described  by  v.  Frankl-Hochwart — tachycardia,  tremor,  and 
Chvostek's  symptoms  (II  and  III),  with  struma  and  vasomotor  excitability. 
This  condition  was  called  "tetanoid"  by  v.  Frankl-Hochwart  (see  above 
for  the  consideration  of  the  hyperthyrosis  or  hypothyrosis  in  tetany). 

3.  Tetany  in  Infectious  Diseases  and  Intoxications 

Tetany  has  been  observed  in  the  most  diverse  infectious  diseases. 
Most  quoted  is  the  frequent  association  of  tetany  in  epidemics  of  typhoid 
fever  {Aran  and  Rahaud).  Tetany  has  also  been  observed  in  angina,  in- 
fluenza, acute  articular  rheumatism,  croupous  pneumonia,  and  many  other 
infectious  diseases.  For  the  most  part  these  cases  occur  in  places  where 
tetany  is  common  and  during  the  time  of  the  occurrence  of  tetany.  There- 
fore it  is  very  probable  that  in  the  majority  of  these  cases  the  infectious 
disease  constitutes  only  the  determining  factor,  that  no  form  sui  generis 
is  present,  but  that  these  cases  belong  to  the  idiopathic  tetany  to  be  de- 
scribed later.  At  all  events  it  is  not  improbable  that  a  generalized  infectious 
process  would  affect  also  the  parathyroids,  and  lead  to  infiltration  or  at  least 
to  parenchymatous  degeneration  of  these  organs,  thus  temporarily  deranging 
their  function. 

In  this  category  belong  the  cases  of  tuberculosis  of  the  parathyroids. 
There  have  been  already  published  numerous  statements  as  to  the  occurrence 
of  this  condition  {Benjamin,  Carnot  and  Delion,  Pepere,  Kdnigstein,  Stumme, 
Schmorl  and  Eggers) .  Carnot  and  Delion,  and  Pepere,  observed  typical  tetanic 
symptoms  in  phthisis,  in  the  days  immediately  preceding  death.  Stumme 
observed  Chvostek's  phenomenon.  These  findings  are  certainly  interesting 
in  consideration  of  the  frequent  occurrence  of  Chvostek's  phenomenon  in 
tuberculosis,  as  mentioned  previously. 

We  can  regard  the  cases  that  occur  in  poisonings  as  a  less  independent 
group.  The  most  diverse  poisons,  such  as  ergotin,  phosphorus,  carbonic 
oxide,  spermin  (Oppenheim),  lead,  morphine,  chloroform,  etc.,  may  lead  to 
14 


2IO  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

an  outbreak  of  tetany.  The  assumption  that  the  poisoning  constitutes  only 
the  determining  factor  has  a  firm  basis  in  the  investigations  of  Rudinger. 
Rudinger  first  determined  that  in  cats  the  peroral  administration  of  calomel, 
the  subcutaneous  administration  of  morphine,  atropine,  tuberculin,  and 
ergotin,  and  the  inhalation  of  ether  does  not  influence  in  any  way  the  elec- 
trical excitabiht}'.  After  these  animals  had  been  placed  in  the  condition  of 
latent  tetany  by  a  partial  parathyroidectomy,  the  administration  of  these 
poisons  led  to  spasms. 

4.  Idiopathic  Tetany  (Occupation  Tetany) 

In  the  description  of  this  form  I  chiefly  follow  the  exposition  of  v.  Frankl- 
Hochwari.  Idiopathic  tetany  shows  the  characteristic  that  it  chiefly  occurs 
in  persons  following  certain  occupations,  that  it  is  especially  frequent  in 
certain  localities,  and  that  it  shows  an  epidemic-like  increase  during  certain 
months.  The  last  observation  was  first  made  by  N.  Weiss  and  v.  Jaksch. 
The  statistics  of  v.  Frankl-Hoclm'art  from  the  years  1880  to  1905  embrace 
five  hundred  and  seventy-six  cases  (among  which,  however,  only  five  hundred 
and  twenty-eight  were  cases  of  occupation  tetany).     Of  these  occurred  in 

Jan.  66       Apr.  in       July  12       Oct.        10 

Feb.  88       May  52       Aug.  9       Nov.       15 

Mar.  137       June  36       Sept.  9       Dec.       31  cases 

The  especial  predisposition  of  the  followers  of  various  occupations  was 
first  mentioned  by  v.  Murdoch,  later  by  von  Jaksch,  Mader,  Hoffmann, 
SchuUze,  and  others.  It  is  especially  cobblers  and  tailors  that  become  af- 
fected with  tetany.  Among  five  hundred  twenty-eight  cases  of  v.  Frankl- 
Hochwart  were  two  hundred  twenty-three  cobblers,  one  hundred  seventeen 
tailors,  thirty-eight  carpenters,  thirty  locksmiths,  thirty  turners  and  the 
remainder  were  divided  among  the  other  occupational  classes.  In  women, 
it  is  especially  the  maids  [i.e.,  lady's  maids]  that  become  affected  (thirty- 
two  of  ninety-nine  female  cases).  Also  soldiers  become  aft'ected  with  it  not 
at  all  rarely  {M attauschek) . 

Another  characteristic  of  occupation  tetany  is  as  has  already  been 
mentioned  that  it  prefers  certain  cities.  It  is  most  frequent  in  Vienna, 
Heidelberg,  and  is  not  rare  in  Budapest;  it  is,  however,  especially  the  lead 
workers  who  become  its  victims  (Jakobi).  ^Moreover,  its  epidemic  exten- 
sion presents  variations.  For  instance  it  was  very  frequent  in  Paris  in  the 
years  1830-1860.  Since  that  time  it  has  been  very  rare  there.  In  Heidel- 
berg also  according  to  the  most  recent  statement  of  Schdnhorn  has  it  become 
rarer.  In  the  other  cities  that  now  harbor  it,  it  shows  a  large  increase  in 
certain  years.  Thus  MaUauschek  observed  an  epidemic  among  soldiers  of 
the  Vienna  garrison  in  the  year  1896.  Outside  these  cities,  tetany  is  sporadic 
nearly  all  over.     In  several  places,  small  epidemics  have  been  observed. 


IDIOPATHIC    TETANY  211 

Idiopathic  tetany  shows  a  great  inchnation  for  relapses.  After  the  first 
attack  it  passes  over  in  the  latent  stage,  and  tends  to  recur  the  next  5'ear  at 
the  time  for  tetany  (acute  relapsing  form  of  tetany,  v.  JakscJi).  There  is  in 
addition  a  chronic  form  in  which  the  disease  never  entirely  disappears. 
The  first  form  may  pass  over  in  the  latter  (see  prognosis) . 

Concerning  the  etiology  of  idiopathic  tetany  we  know  nothing  that  is 
certain.  The  endemic-epidemic  occurrence,  as  is  intelligible,  has  a  priori 
given  occasion  to  the  thought  of  an  infection.  This  is  supported  by  the 
increase  in  temperature  that  occurs  in  the  acute  stages;  I  mentioned  before 
that  this  is  rather  due  to  disturbances  in  the  regulation  of  heat,  which  may 
serve  as  a  partial  manifestation  of  the  irritable  condition  of  the  vegetative 
nervous  system;  it  may  be  said  it  occurs  to  a  much  greater  degree  after 
parathyroidectomy.  Recently  A .  Fuchs  has  pointed  out  the  resemblance  of 
the  clinical  pictures  of  tetany  and  ergotism  (t}-pical  form  of  spasms,  pares- 
thesias, trophic  disturbances,  cataract  formation,  epilepsy,  psychoses,  etc.), 
and  is  inclined  to  refer  occupation  tetany  to  poisoning  with  bad  corn.  Biedl 
comments  on  this  h}-pothesis,  stating  that  there  is  formed  in  the  putrefaction 
of  histidin  an  amino-base  (imidoazolyethylamin)  that  is  identical  with  the 
active  agent  in  ergotin.  I  shall  assume  an  expectant  attitude  with  regard  to 
Fuch's  h}'pothesis,  as  insufficient  facts  are  at  our  command. 

Very  important  for  the  etiology  of  idiopathic  tetany  appears  to  me  a 
contribution  by  McCarrison.  In  certain  valleys  among  the  Himalaya 
mountains  exists  much  epidemic  tetany,  and  indeed  just  in  those  places  where 
there  is  epidemic  goiter.  The  disease  affects  most  solely  women,  and  the  only 
man  in  whom  McCarrison  observed  it  was  not  affected  with  goiter.  The  epi- 
demic of  tetany  takes  on  in  numbers  in  spring,  as  "vsdth  us,  and  is  increased  dur- 
ing pregnancy  and  lactation.  The  goiter  that  predominates  in  this  locality  is 
of  a  marked  degenerative  character.  Numerous  cases  of  tetany  observed  show 
also  signs  of  an  incomplete  myxedema;  very  noteworthy  is  also  the  statement 
that  persons  that  suffer  from  tetany  become  free  of  this  aft'ection  when  they 
go  into  tetany-free  districts,  and  finally  reacquire  the  tetany  when  they  return 
to  the  original  spot.  In  the  light  of  this  observation  seems  to  me  important 
the  fact  that  our  localities  for  tetany.  Vienna  and  Heidelberg,  show  an 
especial  form  of  goiter  in  the  clinical  sense,  further  the  fact  already  men- 
tioned that  i\  F rankl-H ochii'art  has  observed  that  a  great  number  of  cases 
of  tetany  later  show  distinct  symptoms  of  myxedema,  and  finally  the  fact  that 
Kahn  and  /  have  described  the  observation  that  manifestations  of  a  slight 
hyperthyrosis  and  thyroid  swelHng  can  develop  in  the  acute  stage,  or  im- 
mediately at  the  close  of  the  acute  stage.  As  tetany  is  not  frequent  through- 
out in  any  goiter  districts — in  Steiermark  and  Tyrol  it  practically  is  absent, 
and  in  S\^'itzerland  very  rare — we  may  suppose  that  not  every  goiter  noxus 
may  bring  about  idiopathic  tetany,  but  an  especial  goiter  noxus  or  a 
noxus  that  is  similar  to  the  goiter  noxus.     But  even  such  an  assumption 


212  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

is,  as  I  fully  know,  not  satisfactory  in  certain  directions.  It  does  not  explain 
why  tetany  is  so  frequent  in  the  springtime  nor  why  certain  occupations  are 
preferred  in  such  a  striking  manner.  I  beheve  moreover  that  it  would  be 
worth  while  to  pursue  the  problem  further. 

5.  The  Tetany  of  Children 

The  tetany  of  children  is  characterized  by  its  great  multiformity  of  mani- 
festations. The  assumption  of  the  collectivity  of  these  manifestations  is  of 
recent  date.  In  1887  Cheadle  had  already  stated  that  laryngospasm,  tetany, 
and  convulsions  were  only  the  varjdng  expression  of  the  same  "consti- 
tutional morbid  state."  Since  the  year  1890  Eschen'ch  and  v.  Wagner, 
Ganghofner,  and  later  especially  the  school  of  Eschericli  maintained  the  teach- 
ing of  the  belonging  together  of  laryngospasm  and  the  eclampsia  of  child- 
hood, and.  in  spite  of  much  opposition,  have  held  to  these  doctrines,  by  the 
demonstration  of  the  increased  electrical  excitability  and  the  delimination 
from  similar  manifestations  of  another  kind.  The  pathologico-anatomical 
investigations  of  Erdheim  and  Yanasse  seem  adapted  for  estabhshing  this 
\4ew  on  a  safe  basis.  Tetany  of  early  childhood  occurs  chiefly  in  the  third 
to  the  twentieth  month  of  life.  This  is  the  form  that  deviates  from  the  clinical 
picture  of  tetany  of  adults  through  the  multiplicity  of  its  manifestations. 
The  tetany  that  sets  in  from  the  third  year  of  life  on  is  essentially  similar 
to  the  tetany  of  adults.  The  tetany  of  sucklings  which  often  manifests  it- 
self only  through  increased  galvanic,  and  especially  anodic,  h^perexcitability 
is  extraordinarily  frequent  in  rachitic  children  and  especially  also  in  children 
that  have  been  fed  artificially.  This  occurs  almost  always  in  the  cold  time 
of  the  year.  It  shows  a  preference,  as  does  rachitis,  for  northern  countries 
especially,  but  is  distinguished  from  the  tetany  of  adults  by  its  uniform 
extension. 

The  investigations  of  Erdheim  and  Yanasse.  already  mentioned,  have 
furnished  an  interesting  elucidation  for  the  etiology  of  this  form  of  tetany. 
Already  in  1903  Erdheim  had  mentioned  the  finding  of  hemorrhage  in  the 
parathyroids  of  new-born  children,  and  in  1906  he  reported  like  findings  in  two 
of  the  sucklings  that  had  died  of  tetany.  Yanasse  then  examined  system- 
atically the  parathyroids  of  thirty-five  children  who  had  died  at  the  age 
of  fifteen  months.  He  found  that  in  cases  in  which  the  electrical  excitabiUty 
had  been  normal  during  life,  the  parathyroids  were  normal.  In  those  chil- 
dren, however,  in  whom  there  had  existed  electrical  hyperexcitabihty.  he 
found  almost  constantly  hemorrhages  or  the  remains  of  hemorrhages  (in  71 
of  the  104  cases  investigated).  The  hemorrhages  are  demonstrable  at  about 
the  twelfth  month,  and  are  very  probably  to  be  referred  to  trauma  during 
birth.  According  to  the  later  investigations  of  Haberfeld,  the  damaging  in- 
fluence of  the  hemorrhages  does  not  act  so  much  on  the  destruction  of  the 


TETANY    OF   MATERNITY  213 

parathyroid  parenchyma  as  on  the  inhibition  in  growth  of  these  organs  con- 
ditioned by  it.  Erdheim  and  his  collaborators,  on  the  basis  of  their  investi- 
gations, adhere  to  the  view  that  the  tetania  infantum  depends  on  a  hypo- 
parathyroidism, and  that  the  artificial  nourishment  constitutes  only  the 
occasioning  factor.  Erdheim  is  corroborated  by  Peters,  Schmorl,  v.  Verebely 
and  Strada.  Auerbach,  Grosser  and  Betke,  Bliss,  Raymond,  Jdrgensen  and 
others  have  pronounced  against  the  assumptions  on  the  ground  of  patho- 
logico-anatomical  investigations.  Thus  Escherich's  views  in  their  universal 
form  are  to-day  not  generally  shared. 

Heubner  has  grouped  together  the  diseases  mentioned  under  the  less 
prejudicial  name  of  spasmophilic  diathesis. 

The  etiology  of  the  tetany  of  later  childhood  (puerile  tetany  according 
to  Escherich)  is  as  yet  unknown;  perhaps  it  is  identical  with  that  of  the  idio- 
pathic form. 

6.  The  Tetany  of  Maternity 

Under  this  heading  we  understand  the  tetany  observed  in  pregnant, 
child-bearing,  or  puerperal  women,  v.  Frankl-Hochwart  has  collected  fifty- 
three  certain  cases  from  the  literature,  and  adds  to  them  twenty-three  of  his 
own.  Of  these  twenty-eight  affected  women  who  were  pregnant,  nineteen 
occurred  after  the  delivery,  and  twenty-nine  during  the  puerperium.  The 
beginning  of  tetany  in  pregnant  women  occurs  in  the  sixth  to  the  eighth 
month  [of  pregnancy]. 

To-day  maternity  tetany  can  scarcely  make  a  bid  for  the  distinction  of 
a  form  sui  generis.  A  portion  of  the  cases  belong  in  the  group  of  tetany 
after  strumectomy,  the  rest  in  great  part  to  the  group  of  idiopathic  tetany; 
these  come  from  places  affected  with  tetany  and  occur  especially  in  the 
tetany  months,  and  it  seems  to  me  noteworthy  that  there  do  occur  epidemics 
chiefly  in  the  form  of  maternity  tetany.  While  for  example,  according  to 
the  summary  of  ^c?/^r  and  Thaler,  maternity  tetany  is  relatively  rare  in  Vienna 
(at  the  first  gynecological  clinic  at  Vienna  only  nine  cases  of  the  tetany  of 
maternity  were  observed  among  about  30,000  cases) ;  a  great  number  of  the 
cases  described  by  Krajewska  and  also  by  McCarrison  belong  to  this  group. 
In  all  the  forms  the  pregnancy  or  lactation  plays  the  role  of  the  determining 
factor  only.  This  has  been  established  by  numerous  experiments  on  animals. 
At  first  Horsley,  later  Vassale,  Pineles,  Erdheim,  and  especially  Adler  and 
Thaler,  showed  that  in  partially  ectomized  animals  that  show  no  signs  of 
tetany,  the  tetany  comes  to  expression  with  the  progress  of  the  pregnancy. 
In  cases  of  slight  parathyroid  insuf&ciency,  this  may  occur  only  in  the  course 
of  the  second  pregnancy,  or,  as  has  repeatedly  been  observed,  there  may  even 
occur  a  normal  pregnancy  interpolated  between  pregnancies  complicated 
with  tetany.  A  very  interesting  case  of  this  sort  is  reported  by  Meinert. 
In  this  case  there  had  been  two  births  that  were  normal,  then  in  the  third  there 


214  THE    DISEASES    OF    THE    PARATHYROID    GL.\XDS 

was  tetany;  then  there  were  two  more  normal  births,  to  be  succeeded  by  a 
sixth  pregnancy  in  which  the  tetany  recurred.  A  strikingly  marked  atony 
of  the  uterus  has  been  observed  after  the  delivery  in  women  who  have  tetany 
(cases  of  Erdheim  and  of  Neumann).  The  tetany  during  pregnancy  tends 
to  have  a  very  unfavorable  influence  on  the  fetus.  The  birth  of  m.acerated 
fetuses  has  been  reported  several  times  {Pick,  Neumann) ;  or  the  statements  are 
that  the  children  indeed  were  deHvered,  but  soon  died  in  convulsions  {Kocher, 
V.  Frankl-Hochn'art) .  These  last  statements  are  very  important  with  respect 
to  the  investigations  of  Iselin. 

The  question  as  to  why  pregnancy  calls  forth  tetany  in  predisposed  in- 
dividuals is  not  as  yet  fully  explained.  We  may  readily  conceive  that  preg- 
nancy makes  increased  demands  on  all  the  ductless  glands  and  thus  unmasks 
a  latent  insufficiency.  Perhaps  similar  relations  are  to  be  found  with  respect 
to  tetany  combined  \\\t\\  osteomalacia.  In  osteomalacia,  Erdheim  found 
hyperplasia  of  the  parathyroids.  He  assumes  that  in  osteomalacia  there  are 
especial  demands  made  on  these  glands.  The  statement  of  Erdheim  has 
been  often  corroborated.  Schmorl  found  the  parathyroids  normal  in  four 
cases  of  rickets,  but  in  a  case  of  osteomalacia  the  parathyroids  were  markedly 
hypoplastic.  In  three  other  cases  the  parathyroids  were  normal,  although 
Erdheim  points  out  that  the  islands  were  not  examined  with  the  use  of  the 
osmium  stain.  Strada  found  the  parathyroids  enlarged  in  a  case  of  osteo- 
malacia, and  unaltered  in  two  cases;  in  one  case  Bauer  found  in  one  para- 
thyroid an  adenoma,  and  foci  of  proliferation  in  three  others.  Finally  the 
parathyroids  of  twenty-four  individuals  w^re  examined  by  Todyo.  He  found 
hyperplastic  processes  as  described  by  Erdheim  four  times.  In  seven  cases 
of  osteomalacia  they  were,  however,  absent  only  once,  and  in  six  cases  only 
one  parathyroid  was  examined.  In  eleven  cases  of  senile  osteoporosis  he 
found,  on  the  contrary,  hypoplasia  eight  times. 

7.  Tetany  in  Gastrointestinal  Diseases 

Tetany  is  observed  in  the  most  diverse  gastric  and  intestinal  affections. 
I  mention  only  acute  dyspepsia,  acute  and  chronic  enteritides,  and  helmin- 
thiasis. Especially  are  those  cases  brought  into  relief  in  which  on  account 
of  some  obstruction  there  occurred  a  dilatation  of  the  stomach,  or  (in  rare 
cases)  a  dilatation  of  the  intestine,  and  a  stagnation  of  the  gastric  and  in- 
testinal contents.  From  the  great  group  of  gastrointestinal  tetany  a  number 
of  cases  are  to  be  singled  out  in  which  the  gastrointestinal  disturbances  con- 
stitute only  one  symptom  of  the  tetany.  I  would  agree  with  Chvostek  that 
these  cases  are  not  at  all  rare.  This  has  been  taken  up  in  detail  in  the  con- 
sideration of  the  symptomatology.  In  a  further  group  of  cases  an  indisposi- 
tion of  the  stomach  or  intestines  may  constitute  the  determining  factor  for 
the  tetany. 


TETANY    IN    GASTROINTESTINAL   DISEASES  215 

An  especial  interest  attaches  to  that  form  which  occurs  when  the  gastric 
or  intestinal  disturbance  has  existed  for  a  long  time.  Attention  to  this 
form  was  directed  first  by  Kussmaul.  Since  that  time  there  have  been  pub- 
lished numerous  reports  concerning  it  (Fleiner,  Fr.  Muller,  Gerhardt,  Bouveret 
and  Devic,  Ewald,  Albu,  Schlesinger,  v.  Frankl-Hochwart,  Rudinger  and  Jonas, 
Wirth).  The  most  various  conditions  have  been  found:  Cicatrized  ulcer  of 
the  pylorus  or  the  duodenum,  hour-glass  stomach,  mahgnant  processes 
(such  as  carcinoma  or  sarcoma)  in  the  neighborhood  of  the  pylorus,  or 
tumors  of  the  gall-bladder  or  of  the  pancreas  that  lead  to  stenosis,  torsion 
of  the  stomach,  acute  paralytic  dilatation  of  the  upper  small  intestines, 
in  children  dilatation  of  the  colon,  etc. 

There  has  also  been  reported  a  group  of  cases  of  dilatation  of  the  stomach 
without  demonstrable  stenosis.  I  mention  from  the  newer  literature  only 
the  cases  of  Ferrannini  and  of  Fleiner. 

The  tetany  that  occurs  in  all  these  conditions  may  be  quite  rudimentary. 
Not  rarely,  however,  it  is  of  the  most  severe  forms,  forms  that  are  attended 
with  universal  spasms  and  loss  of  consciousness. 

Bouveret  and  Devic  distinguish  a  simple  form  attended  with  paresthesia 
and  typical  spasms  of  the  extremities,  and  a  "  tetanisme  plus  ou  moin  general- 
ise" that  may  lead  to  dyspnea  and  death  from  asphyxia  principally  through 
involvement  of  the  muscles  of  respiration,  and  a  form  attended  with  loss  of 
consciousness  and  coma.  These  severe  forms  of  stomach  tetany  leave  the 
prognosis  always  somewhat  doubtful.  The  present  statistics  show  a  mor- 
tality of  about  60-70  per  cent. 

Numerous  hypotheses  have  been  brought  forward  to  explain  this  form. 
In  a  certain  number  of  the  cases  perhaps  an  affection  of  the  gastrointestinal 
tract  may  play  the  determining  role.  This  may  be  likely  through  the 
circumstance  that,  as  the  figures  of  v.  Frankl-Hochwart  show,  a  great  number 
of  these  cases  occur  during  the  tetany  months.  On  the  grounds  of  this  ob- 
servation Rudinger  and  Jonas  have  upheld  the  supposition  that  the  tetany  of 
gastrodilatation  is  nothing  more  than  tetany  acquired  in  the  course  of  a 
gastrodilatation.  This  explanation  does  not  seem  to  me  to  be  entirely 
satisfactory.  Before  everything  else,  it  is  striking  that  this  form  of  tetany 
is  less  confined  to  the  tetany  districts.  Kussmaul  supposed  that  the  tetany 
was  caused  by  a  thickening  of  the  blood,  due  to  the  frequent  vomiting  and  the 
diminished  absorption  of  water.  Fleiner  has  adopted  this  theory,  pointing 
to  the  hyperglobulia  observed  by  Fr.  Muller  and  also  himself.  This  hy- 
perglobulia  is,  however,  as  we  have  already  seen,  not  the  cause  of  tetany 
spasms,  but  their  effect.  Gerhardt,  Palliard,  Ewald,  Albu,  and  others  have 
supposed  that  toxic  substances  bring  about  the  tetany,  their  origin  being  due 
to  the  stagnation  of  the  gastric  and  intestinal  contents  (autointoxication 
theory).  The  finding  of  diamines  in  the  stomach  contents  and  in  the  urine 
of  such  patients  means  nothing,  as  they  are  also  found  there  in  other  diseases. 


2l6  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

It  is  certain,  however,  that  in  many  cases,  the  tetany  promptly  disappears  on 
combating  of  the  stagnation  (for  example  washing  out  of  the  stomach). 
The  explanation  of  this  subject  has  as  j^t  received  no  elucidation  from 
pathologico-anatomical  investigations.  Erdheim  found  the  parathyroids 
entirely  normal,  first  in  a  case  of  severe  gastric  tetany,  then  in  a  second  case 
with  slight  gastric  manifestations,  and  third  in  the  case  of  tetany  in  the 
course  of  enteritis.  MacCallum  in  a  case  of  gastric  tetany  found  five  rather 
large  parathyroids  whose  cells  showed  abundant  mitoses.  This  he  re- 
garded as  hyperplasia.  Kinnicutt  found  in  a  case  of  gastric  tetany  the 
parathyroids  normal.  It  seems,  therefore,  that  in  a  group  of  these  cases 
there  is  present  only  a  relative  insufficiency  of  the  function  of  the  para- 
thyroids with,  however,  markedly  increased  demands  on  them;  we  should 
consider  further  the  possibility  that  in  high-grade  stagnation  in  the  gastro- 
intestinal tract  substances  are  formed  and  absorbed  that  increase  the  ex- 
citability of  the  nervous  system  so  markedly  that  under  circumstances  the 
action  of  the  parathyroids  no  longer  suffice;  we  must  also  assume,  however,  a 
certain  predisposition  of  the  individuals  affected,  as  conditions  of  stagna- 
tion in  gastrointestinal  conditions  are  rather  frequent,  while  complication 
with  tetany  is  very  rare. 

If  we  pass  in  review  what  has  been  said  concerning  the  individual  forms 
of  tetany  and  their  etiology,  we  find  that  we  cannot  deny  that  the  view  that 
all  forms  of  tetany  may  be  grouped  together  from  the  point  of  view  of 
relative  or  absolute  insufficiency  of  the  parathyroids  is,  as  a  result  of 
pathological  anatomy,  not  sufficiently  proved.  All  the  rest  of  the  patho- 
logico-anatomical findings  that  up  to  the  present  have  been  brought  into 
relief  in  tetany,  findings  such  as  alterations  in  the  ganglion-cells  of  the  spinal 
column,  in  the  marrow,  or  in  the  nerve  fibers  themselves,  have  been  incon- 
stant. As  yet  unelucidated  as  to  its  significance  is  the  finding  of  a  premature 
sclerosis  of  the  fine  and  finest  cerebral  vessels,  especially  in  the  medulla 
of  the  cerebrum  and  in  the  cerebellum,  such  as  A.  Pick  pointed  out  in  four 
cases  of  chronic  tetany. 

Differential  Diagnosis.— We  distinguish  an  acute  relapsing  and  an  acute 
recurring  form  of  tetany.  We  should  also  appropriately  distinguish  be- 
tween a  manifest  and  latent  tetany  unattended  with  spasms,  and  finally 
between  fully  developed  form  of  the  formes  frustes  (the  expression  tetanoid 
I  regard  as  less  to  the  purpose) ;  it  is  the  latter  dift'erentiation  that  is  attended 
with  dift"erential  diagnostic  difficulties.  In  general,  the  diagnosis  of  tetany  is 
easy,  as  its  most  important  criterion,  the  galvanic  hyperexcitability.  has  as 
yet  been  observed  in  no  other  condition.  As  has  previously  been  mentioned, 
Erh's  phenomenon  may  be  temporaril}'  absent  even  in  the  acute  stage.  In 
such  cases  great  value  can  be  attached  to  Chvostek^s  phenomenon  only 
when  it  is  pronounced.  If  in  addition  there  are  present  paresthesias  in 
the  territory  of  the  ulnar  nerve  and  complaints  as  the  sensations  of  tension 


TETANY    IN    GASTROINTESTINAL   DISEASES  217 

in  the  hands  and  feet,  the  diagnosis  of  tetany  appears  to  be  very  Kkely;  often 
there  occur  in  the  further  course  of  the  disease  fibrillary  contractions,  or 
Trousseau' s  phenomenon,  or  only  transitorially  a  slight  degree  of  heightened 
galvanic  hyperexcitability  thus  making  entirely  certain  the  diagnosis. 
Not  rarely,  during  the  tetany  season,  Reichmann's  disease  may  be  attended 
with  quite  rudimentary  forms  of  tetany. 

V.  Frankl-Hochwart  and  Fleiner  have  regarded  certain  cases  of  gastric 
tetany  described  in  the  literature  as  spurious,  as  they  showed  only  sensa- 
tion of  tension  in  the  hands,  with  the  absence  of  ErVs  phenomenon.  During 
the  last  few  years  I  have  observed  six  cases  of  gastric  tetany  (see  also  Falta 
and  Kahn) ;  in  almost  all  I  was  dealing  with  a  typical  Reichmann's  disease 
with  marked  dilatation  of  the  stomach  and  increased  peristalsis,  indeed  even 
antiperistalsis,  phenomena  that  retrogress  in  many  such  cases  on  appro- 
priate treatment.  In  some  galvanic  hyperexcitability,  mostly  of  a  slight 
grade,  was  present  quite  transitorily.  However,  the  paresthesias  and  the 
sensation  of  tension  outlasted  Erb's  phenomenon  for  a  long  time.  Therefore, 
in  the  formes  frustes  we  may  miss  Erb's  phenomenon,  even  on  repeated 
examinations.  We  fully  recognize  its  prominent  importance  for  the  diag- 
nosis; there  do  occur,  however,  isolated  cases  in  which  it  is  absent  and 
in  which  the  diagnosis  tetany  can  be  established  in  spite  of  this  fact. 

Concerning  diseases  that  may  be  confused  with  tetany  I  mention  only 
the  following:  Tetanus  is  readily  distinguished  from  it  by  the  increase  in 
reflexes,  by  the  noninvolvement  of  the  hands,  and  by  the  absence  of  the 
typical  symptoms  of  tetany.  Also  the  delimitation  from  meningitis,  from 
acroparesthesia  in  chronic  poisonings  and  from  occupational  spasms  is 
always  easy,  as  in  these  diseases  the  typical  distinguishing  symptoms  of 
tetany  are  absent.  Hysteria  may  occur  combined  with  tetany,  and  in  such  a 
way  that  tetany  spasms  and  hysterical  spasms  are  present  simultaneously,  or 
the  hysterical  spasms  may  come  to  the  fore  on  the  retrogression  of  the  tetany, 
or  hysteria  alone  may  exist  simulating  tetany  (pseudotetany)  {E.  Freund, 
H.  Curschmann,  F.  Ckvostek).  In  this  form,  naturally  Erb's  phenomenon 
is  absent,  but  hysterical  stigmata  are  present.  The  pseudotetany  attacks 
may  simulate  the  true  tetany  attacks  in  an  illusory  manner.  The  uni- 
lateral occurrence  of  the  spasms  would  rather  point  to  the  thought  of  hys- 
teria. Yet  it  should  not  be  forgotten  that  a  few  true  cases  of  hemitetany 
have  been  known  (H.  Freund,  v.  Frankl-Hochwart,  v.  Jaksch,  E.  Fretmd,  et 
al.) .  Too,  Trousseau's  phenomena  is  often  simulated  illusorily.  Especially 
to  be  considered  is  the  absence  of  the  paresthesias  usually  attending  tetany 
attacks,  and  of  Erb's  phenomenon,  and  the  presence  of  fibrillary  contrac- 
tions. If  these  cases  of  pronounced  hysterical  symptoms  are  added  to 
a  true  tetany,  Erb's  phenomenon  is  decisive. 

In  the  differential  diagnosis  between  epilepsy  and  tetany  it  is  especially 
important  to  determine  whether  epileptiform  convulsions  belong  to  tetany 


2l8  THE    DISEASES    OF    THE    PARATHYROID    GLAXDS 

or  whether  there  exists  a  true  epilepsy  in  addition  to  the  tetany.  Especial 
attention  must  be  directed  to  the  aura,  to  the  incontinence  of  urine  and  feces 
during  the  attack  and  to  the  postepileptic  stupor.  Loss  of  consciousness  in 
tetany  is  very  rare,  in  epilepsy  it  is  the  principal  symptom.  In  similar 
fashion  a  case  of  tetany  with  symptoms  of  myotonia  must  be  investigated 
with  regard  to  the  cardinal  symptoms  of  true  myotonia  (myotonic  reaction) . 

The  galvanic  hyperexcitability  is  important,  according  to  Escherich, 
for  difterentiation  from  eclamptic  convulsions  of  the  years  of  childhood. 

The  prognosis  for  the  different  clinical  forms  of  tetany  is  not  the  same, 
and  in  strumiprivic  tetany  the  prognosis  quoad  vitam  may  be  very  un- 
favorable. To-day  such  cases  scarcely  come  into  consideration.  The 
prognosis  of  idiopathic  tetany  quoad  sanitationem  was  formerly  regarded  as 
favorable.  Since  v.  Frankl-Hochwart  has  reviewed  his  cases  the  views  as  to 
this  point  have  changed  considerably.  Of  fifty-five  cases  only  nine  were 
entirely  healthy,  seven  showed  chronic  tetany,  general  nervousness  and 
chronic  invalidism,  nineteen  showed  slight  tetany  symptoms  and  trophic 
disturbances,  six  showed  chronic  invalidism  without  symptoms  of  tetany, 
eleven  had  died  four  to  eleven  years  after  the  outset  of  the  tetany.  Saiz 
furnishes  similar  unfavorable  statistics.  He  states  that  of  nine  cases  only 
one  remained  free  of  distress,  and  that  also  this  individual  had  sustained  a  re- 
currence. Cases  of  death  from  tetany  of  maternity  have  been  reported 
{Trousseau.  Scliundlechner,  Blazicek,  et  al.).  Also  transition  into  chronic 
tetany  has  been  observed,  v.  Frankl-Hocliwart,  Adler,  and  Thaler  and 
Novak,  in  contradistinction  of  Fellner,  hold  therefore  the  prognosis  as  doubt- 
ful. Especially  unfavorable  is  the  prognosis  in  tetania  gastrica;  here  it 
happens  that  the  stomach  affection  itself  frequently  influences  the  prognosis 
unfavorably.  Also  in  the  tetany  of  childhood  the  revisions  of  the  more 
recent  period  have  furnished  rather  unfavorable  results  as  to  the  length 
of  life  and  especially  as  to  the  further  development  {Escherich,  Thiemich, 
Birk,  and  Potpetschnigg). 

According  to  Escherich,  25  per  cent,  of  the  nurslings  at  the  hospitals  who 
are  sick  with  tetany  die,  and  Thiemich  and  Birk  in  Breslau  and  Potpetschnigg 
in  Graz  have  concerned  themselves  with  the  later  fate  of  children  who  have 
been  sick  with  tetany.  Both  statistics  come  to  the  result  that  a  not  in- 
considerable number  of  such  children  soon  die.  Those  investigated  were 
only  rarely  quite  normal.  In  the  majority  of  cases  they  showed  disturbances 
of  the  psychical  and  intellectual  development  and  especially  remaining  be- 
hind in  the  development  of  speech. 

The  treatment  of  tetany  should  be  concerned  first  of  all  with  efforts  to 
replace  the  lacking  parathyroid  function  or  to  improve  the  insufficient  para- 
thyroid function.  It  is  a  pity  that  up  to  the  present  all  attempts  have  been 
futile.  The  substitution  therapy  that  was  so  valuable  in  thyroid  insufficiency 
has  in  this  case  up  to  the  present  led  to  no  certain  result.     It  is  intelligible 


TETANY   IN   GASTROINTESTINAL  DISEASES  219 

to-day  why  the  thyroid  medication  formerly  employed  in  tetany  was  without 
results.  It  is  remarkable,  however,  that  no  decisive  results  are  obtained  by 
the  administration  of  subcutaneous  employment  of  dried  parathyroid  gland 
or  of  extracts  of  parathyroids.  The  favorable  statements  of  a  few  authors 
(parathyroid  tablets,  Marinesco,  Lowenthal,  Wieprecht;  parathyroantitoxin, 
Vassale)  stand  in  contradiction  to  the  negative  results  of  the  exact  trials  of 
Pineles  and  the  statements  of  many  other  authors. 

Pineles  found  that  neither  stomachal,  nor  subcutaneous,  nor  intra- 
peritoneal administration  of  parathyroid  extract  in  large  doses  served  to 
influence  in  any  way  parathyroprivic  tetany.  Again,  the  feeding  of  very 
large  amount  of  the  extract  of  the  parathyroids  of  horses,  remained  without 
results  in  human  beings.  One  is  reminded  of  the  negative  results  of  pancreas 
feeding  (islands  of  Langerhans)  in  diabetes.  The  parathyroids  are,  like  the 
pancreas,  no  storage  glands. 

The  attempts  to  transplant  the  parathyroids  at  first  awakened  great 
hopes;  v.  Eisehberg  and  later  Payr  transplanted  the  thyroid  gland  in  the 
abdominal  wall  or  in  the  spleen  and  (on  account  of  associated  transplantation 
of  the  parathyroids)  prevented  the  outbreak  of  the  tetany.  Enderlen  first 
showed  microscopically  that  the  parathyroids  transplanted  with  the  thyroid 
gland  remained  capable  of  functionating,  in  that  in  part  they  regenerated. 
Since  that  time  numerous  transplantations  have  been  undertaken  by  Biedl, 
Pfeiffer  and  Meyer,  Halstead,  Harvey,  Cristiani,  Leischner,  et  al.) ;  favorable 
results  have  also  been  reported  in  man  (first  by  v.  Eiselsberg);  favorable 
results  were  reported  hy  Pool-Kocher  (transplantation  into  the  bone  marrow), 
V.  Garre,  Boese  and  Lorenz,  and  Danielsen.  The  clinic  of  v.  Eiselsberg  later 
met  with  unfavorable  results.  On  this  account,  the  question  was  restudied 
by  Leischner  and  KoJiler,  who  concluded  that  the  parathyroids  behave 
quite  similarly  to  the  thyroid,  that  is,  that  only  autotransplantation  is  at- 
tended with  favorable  results;  while  on  homiotransplantation  it  is  true 
that  the  parathyroids  functionate  for  a  time  at  first,  but  later  they  become 
absorbed. 

The  administration  of  calcium  salts  has  been  regarded  by  MacCallum  and 
Vbgtlin  as  a  causal  therapy.  Theoretically,  the  condition  of  excitability  in 
ectomized  animals  should  become  dampened.  Improvement  is  reported  by 
Curschmann  in  three  cases  of  tetany  in  man,  and  by  E.  Meyer  in  a  case  of 
tetany  of  pregnancy.  KaJin  and  /  studied  the  excitability  of  the  nerves  at  in- 
tervals of  two  to  three  hours,  and,  after  the  administration  of  even  a  large 
amount  of  calcium  lactate  never  observed  a  distinct  influence  on  the  same. 
Also  the  intramuscular  administration  of  "Kalzine"  {v.  Muller  and  Saxl) 
was  ineffective.  If  the  assumption  that  in  tetany  the  assimilation  of  calcium 
in  the  nervous  system  is  disturbed  holds  good,  it  seems  to  me  that  the  nega- 
tive results  become  intelligible;  the  person  with  tetany  behaves  against  in- 
creased administration  of  calcium  just  as  a  patient  with  pancreatic  diabetes 


2  20  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

behaves  against  increased  administration  of  sugar.  We  should  expect,  on 
the  contrary,  in  conditions  of  increased  dissipation  of  calcium,  a  result  from 
the  calcium  administration.  Perhaps  we  may  explain  in  this  manner  the 
favorable  results  of  calcium  treatment  in  Basedow's  disease. 

There  therefore  remains  for  the  treatment  of  tetany  only  symptomatic 
therapy,  a  therapy  that  likewise  is  almost  ineffective.  Weak  sedatives  such 
as  the  bromides  and  valerian  are  especially  ineffective.  In  severer  cases  we 
can  occasionally  ameliorate  the  condition  by  the  use  of  chloral.  Levi 
claims  to  have  had  good  results  through  blood-letting,  and  Narhut  through 
lumbar  puncture.  The  means  that  have  proved  best  are  rest  in  bed,  diet 
poor  in  meats,  protracted  warm  baths,  and  roborants.  The  phosphorus 
liver  oil  had  been  especially  recommended  in  cases  complieated  with  osteo- 
malacia. In  the  tetany  of  sucklings,  Escherich  recommends  the  interpolation 
of  days  with  just  adequate  diet;  it  is  especially  important  to  substitute 
natural  feeding  for  cow's  milk  whenever  possible.  W^orthy  of  notice  is  the 
statement  of  McCarrison  that  some  cases  of  tetany  disappeared  when  the 
patient  moved  to  another  place.  In  women  conception  should  be  pre- 
vented or  even  pregnancy  interrupted.  Certain  drugs,  such  as  ergotin, 
are  to  be  avoided  in  the  tetany  of  pregnancy  {Novak) . 

Gastric  tetany  deserves  an  especial  consideration.  Here  the  question  of 
operation  (gastroenterostomy)  has  met  with  lively  discussion.  While  Albii 
recommends  operation  as  soon  as  possible,  Fleiner  would  first  await  the  results 
of  internal  therapy.  Also  Chvostek  favors  internal  treatment.  The  results 
of  the  surgical  treatment  now  seem  very  much  to  encourage  this  method  of 
treatment.  According  to  the  latest  statistics  by  Wirth,  of  twenty-one  oper- 
ated cases,  seventeen  remained  permanently  cured,  while  according  to 
older  statistics  of  Alhu  the  mortality  of  cases  treated  internally  reached  77  per 
cent.  The  question  is,  however,  rather  more  complicated  than  one  would 
gather  from  these  statistics.  In  case  of  assured  pyloric  stenosis,  operation  is 
indeed  not  to  be  rejected,  the  question  is  only  whether  operation  should  be 
undertaken  immediately  or  whether  it  should  be  postponed  until  we  find 
that  we  can  accomplish  no  good  by  attempts  to  improve  through  internal 
treatment.  Much  will  depend  upon  whether  gastric  lavage  can  be  borne. 
The  chief  difticulty  is  met  with  in  the  diagnosis  of  the  pyloric  stenosis. 
Cases  of  Reichmann's  disease  may  present  all  the  symptoms  of  pyloric 
stenosis — increased  peristalsis  in  front  of  a  fluoroscope,  indeed  even  anti- 
peristalsis.  Even  in  cases  of  true  gastric  tetany  we  saw  not  only  a 
disappearance  of  the  tetanic  symptoms  but  also  a  lessening  of  the  size  of  the 
stomach  and  a  cessation  of  the  spasm  of  the  pylorus — this  as  the  result  of 
gastric  lavage  every  evening,  and  the  administration  of  a  dry  diet  rich  in 
fats  and  of  enemas  to  satisfy  thirst.  In  such  cases  perhaps  operation 
would  be  without  curative  results. 


ADDENDUM  2  21 

b.  Conditions  of  Hyperfimction  of  the  Parathyroids 

Certain  cases  of  adenoma  of  the  parathyroids  are  known,  without  there 
having  been  found  conditions  that  would  be  regarded  as  those  of  hyper- 
function  (Erdheini).  Also  the  tumors,  in  size  up  to  that  of  a  child's  head, 
described  by  Benjamin,  Hulst,  and  de  Santi,  were  attended  with  symptoms 
that  were  purely  local,  and  otherwise  remained  without  symptoms.  In 
paralysis  agitans,  which  was  brought  into  relation  with  the  parathyroids  by 
Roussy  and  Clunet,  Erdheim  found  the  parathyroids  normal  in  three  cases. 
Lundhorg  and  Chvostek  ascribed  myasthenia  pseudoparalytica  to  hyper- 
function  of  the  parathyroids.  Chvostek  sought  to  establish  that  the  clinical 
pictures  of  myasthenia  and  tetany  were  diametrically  opposed  to  each 
other.  Both  would  seem  to  affect  the  voluntary  muscles  with  nonin- 
volvement  of  the  sphincters.  The  electrical  behavior  in  myasthenia  is 
directly  opposite  to  that  in  tetany;  and  in  the  one  is  found  fatigue  of  accom- 
modation, in  the  other  accommodation  spasm.  Each  sometimes  accom- 
panies myxedema  or  Basedow's  disease.  The  finding  of  the  collection  of 
cellular  infiltrations  and  of  discontinuous  fatty  degeneration  of  the  muscle 
fibers,  that  is  extraordinarily  frequent  (for  literature  see  Marburg),  points 
rather  to  the  fact  that  myasthenia  belongs  more  to  the  diseases  of  the 
muscular  system;  moreover,  Haberfeld  recently  has  been  unable  to  find  any 
alteration  of  the  parathyroids  in  the  cases  of  myasthenia  gravis  (see  also  the 
first  chapter). 

Addendiun 

The  author's  criticism  that  some  of  the  negative  results  ofthyropara- 
thyroidectomy  may  be  due  to  the  leaving  behind  of  inaccessible  parathyroids 
or  portions  of  parathyroids  seems  also  to  the  opinion  of  MacCallum,  Thomson, 
and  Murphy.  At  all  events  it  appears  that  adult  herbivorous  animals  (the 
sheep,  Simpson)  are  capable  of  sustaining  thyroparathyroidectomy  without 
appreciable  effect,  although  in  Simpson's  experiments  the  lambs  that  were 
operated  on  developed  acute  tetany  and  died. 

The  results  obtained  by  Mustard  on  transection  of  the  spinal  cord  agree 
with  BiedVs  and  MacCallum's  in  that  they  are  diametrically  opposed  to 
Munk's  and  to  Falta's  as  to  noncontinuance  of  tonic  contractions  in  the 
parts  below  the  seat  of  cutting  after  transection  of  the  spinal  cord.  It 
is  a  pity  that  the  divergence  in  results — w^hether  they  are  due  to  differences 
in  interpretation  or  dift'erences  in  technique — have  not  as  yet  been  explained. 

Hoskins  and  Wheeler  have  tested  the  eft'ects  of  the  injection  of  nicotin, 
adrenalin,  and  pituitrin  in  parathyroidectomized  dogs,  and  have  found  that 
in  these  dogs  there  is  a  marked  increase  of  vasomotor  irritability  aft'ecting 
all  components  of  the  vasomotor  mechanism,  sympathetic  cells,  myoneural 
junctions,  and  musculature. 


222  THE    DISEASES    OF    THE    PARATHYROID    GLANDS 

Under  hill  and  Blatherweck  show  that  during  the  tetany  which  develops 
after  thyroparathyroidectomy,  glycogen  disappears  entirely  from  the  liver 
and  the  sugar  content  of  the  blood  is  markedly  lowered  or  may  even  be  re- 
duced to  zero.  It  is  probable  that  this  action  may  be  ascribed  to  the  lack 
of  parathyroid  tissue,  since  the  phenomena  may  be  observed  when  all  the 
parathyroids  are  removed  and  some  thyroid  tissue  remains. 

Poll  and  Turnure  have  transplanted  a  parathyroid  into  the  preperitoneal 
tissue  behind  the  sheath  of  the  rectus  muscle,  in  a  case  of  tetany  due  to 
supposed  operative  removal  of  the  parathyroids,  with  apparently  good 
results,  including  cessation  of  the  tetany. 

Following  the  idea  suggested  to  him  by  Meltzers  experiments,  Berend 
treats,  with  unusual  success,  cases  of  tetany  with  subcutaneous  injections  of 
magnesium  sulphate  solution  (15.20  cgm.  magnesium  sulphate  per  kilogram 
of  body  weight).  The  electrical  hyperirritability  and  the  carpopedal  spasm 
diminish,  and  there  is  a  shortening  of  the  disease's  duration.  The  treat- 
ment is  combined  with  a  salt-free  diet.  An  8%  solution  of  magnesium 
sulphate  should  be  used,  and  the  water  for  dissolving  it  should  be  freshly 
distilled.      15.20  c.c.  of  this  solution  is  the  usual  dose  for  a  young  infant. 

References 

Simpson  (5.).  The  influence  of  age  following  thyroparathyroidectomy.  Proc.  Soc. 
Experim.  Biol,  and  Med.,  Vol.  IX,  1911-1912,  pp.  2-4. 

Mustard  {H.  J.).  A  study  of  certain  tonic  and  reflex  nervous  impulses  as  factors  in 
parathyroid  tetany.     Am.  J.  Physiol.,  1911-1912,  XXIX,  31 1-3 16. 

Hoskins  {R.  G.)  and  Wheelan.  Parathyroid  deficiency  and  sympathetic  irritability. 
Am.  J.  Physiol.,  Vol.  XXXIV,  No.  3,  June  i,  19 14. 

Underhill  {G.  P.)  and  Blatherweck  {N.  P.).  The  influence  of  thyreopurathyroidec- 
tomy  upon  the  sugar  content  of  the  blood  and  the  glycogen  content  of  the  liver.  J.  Biol. 
Chem.,  Vol.  XVIII,  No.  i,  June,  1914,  pp.  87-90. 

Pool  and  Turnure.  Annals  of  Surgery,  \'ol.  L\'I,  2,  191 2;  \'ol.  L\T,  Nov.,  191 2, 
No.  2,  pp.  804-807. 

Berend  (N.).  Die  Magnesiumsulfat  behandlung  der  spasmophilic  Kriimpfe.  Monat- 
schrift  fur  Kinderheil  Kunde  Bd.  12.  Originalien.  1914,  pp.  269-331.  Also,  \'er- 
handlungen  der  Gesellschaft  deutscher  Naturforscher  und  Arzte.  Pt.  2,  2nd  half.  1913, 
p.  596-598. 


CHAPTER  V 
THE  DISEASES  OF  THE  THYMUS  GLAND 

It  has  not  been  long  that  the  thymus  gland  has  been  classed  with  the 
hormonopoietic  system.  Originally  it  was  regarded  as  a  constituent  of  the 
lymphatic  apparatus. 

Anatomy  and  Embryology. — The  thymus  gland  develops  as  a  paired 
organ  from  the  ventral  part  of  the  third  branchial  cleft.  fSee  illustration  3. 
p.  53).  The  pairs  Unite  very  early;  at  birth  the  organ  hes  behind  the 
sternum,  backward  as  far  as  the  pericardium,  reaching  above  somewhat 
higher  than  the  jugular  notch.  In  the  human  being  there  may  occur  ac- 
cessory lobes  of  the  thymus  which  may  be  either  independent,  or  be  united 
with  the  thyroid  gland,  or  even  the  thymus  gland  itseh.  The  thymus  gland 
is  of  entodermal  origin;  although  at  present  there  is  no  unity  of  opinion 
with  regard  to  the  origin  of  the  pictures  resembhng  lymphocytes  found 
in  the  completed  thymus  and  especially  in  its  cortex.  Since  the  inves- 
tigations of  Hammar  the  entodermal  origin  of  the  polymorphic  fixed 
reticular  elements  lying  chiefly  in  the  meduha,  and  of  the  so-called  HassaVs 
corpuscles  stands  assured.  Stohr  regards  the  origin  of  the  th3^mus  lympho- 
cytes as  due  to  division  of  the  epithehal  cells  while  recently  Hammar  and 
Maximoiv.  following  the  older  assumption  of  His  and  Stieda,  adhere  to  the 
assumption  of  a  secondary  ingrowth  of  mesodermal  pictures.  According  to 
the  latter  view,  the  thymus  gland  therefore  belongs  to  the  lymphatic  ap- 
paratus; there  is  found  in  it  a  ''symbiosis  of  cehs  of  the  different  germinal 
layers;"  it  is  concerned  with  the  production  of  lymphocytes.  According  to 
Nagele  it  is  indeed  the  principal  site  in  the  formation  of  the  lymphocytes  in 
early  hfe.  The  same  author  states  that  this  view  is  also  favored  by  phylo- 
genetic  factors,  for  in  the  amphibians  the  thymus  is  the  source  of  lymphocytes 
when  the  lymph  glands  are  still  absent.  The  statement  of  Ivar  Bang  that  the 
thymus  gland  contains  at  least  five  or  six  times  more  nucleinate  than  the 
lymphatic  glands  does  not  speak  unconditionally  against  this  assumption, 
as  the  analysis  included  the  epithelial  elements. 

The  weight  of  the  thymus  gland  increases  after  birth,  according  to  the 
statement  of  Hammar.  v.  Sur\\  Schridde.  Roiiconi,  Pappenheimer.  and  others, 
the  growth  ceasing  only  with  the  beginning  of  sexual  maturity;  the  thymus 
tissue  gradually  atrophies  and  is  partly  replaced  by  fat,  although  appreciable 
remnants  of  thymus  tissue  are  retained  until  late  hfe.  In  late  Hfe  too  were 
found,  by  Hammar.  mitotic  proliferation  of  lymphocytes  and  new  formation 

223 


2  24  THE    DISEASES    OF    THE    THYMUS    GLAND 

of  HassaVs  corpuscles.  In  addition  to  this  involution  of  age  an  accidental 
involution  also  occurs;  Hammar  and  Jonson  have  shown  that  in  fasting  ani- 
mals the  weight  of  the  thymus  gland  reduces  very  rapidly,  especially  through 
loss  of  lymphocytes.  Also  in  the  melting  down  of  the  thymus  gland  on 
irradiation  with  X-rays,  the  reticulum  shows  itself  much  more  resistant  than 
the  lymphocytes.  The  accidental  involution  is  found  among  chronic  dis- 
eases that  lead  to  marasmus.  It  is  especially  well  expressed  in  pedatrophy 
{Farret).  Also,  according  to  Hammar,  accidental  involution  may  occur  in 
older  people,  an  evidence  that  glandular  tissue  capable  of  functionating  has 
still  been  present. 

Physiology. — The  question  as  to  whether  the  thymus  gland  is  an  organ 
important  for  the  life  of  the  organism  has  not  until  recent  times  received 
a  uniform  answer.  Friedleben,  Langcrhans,  and  others  saw  animals  in  which 
the  thymus  gland  had  been  removed  go  undisturbed  in  their  development, 
while  other  authors  on  the  contrary,  of  whom  I  here  mention  only  Tarulli 
and  LoMonaco,  Ghika,  Cozzolino,  Basch,  Sommer  and  Florken;  Rami  and 
Tandler  saw  occur  in  dogs,  rabbits,  cats,  and  other  animals,  temporary 
serious  disturbances  of  growth  which  later  disappeared.  The  most  recent 
investigations  are  those  of  Klose  and  Vogt  and  of  Matti.  The  investigations 
make  it  very  likely  that  the  disturbances  mentioned  can  no  longer  disap- 
pear when  the  extirpation  of  the  thymus  gland  has  been  done  on  very 
young  animals  only  a  few  days  old. 

Klose  and  Vogt  operated  on  twenty-five  dogs.  The  phenomena  observed 
are  briefly  as  follows:  After  the  latent  stage  of  about  fourteen  days  the  ani- 
mals gradually  showed  a  spongy,  soft  skin,  a  "pasty  habitus."  They  began 
to  remain  behind  in  growth  on  account  of  a  lessened  growth  in  length  of  the 
extremities.  The  bones  were  distinctly  more  flexible.  In  agreement  with 
Basch,  Klose  and  Vogt  found  that  the  ossification  is  retarded  and  that  if 
the  bones  are  fractured  callus  formation  is  very  poor  or  does  not  occur  at 
all.  The  ash  contents  of  the  bones  is  essentially  diminished.  Basch  also 
found  that  in  this  stage  the  elimination  of  calcium  is  essentially  increased. 

The  hyperexcitability  to  galvanism  which  Basch  found  in  thymectomized 
animals  is  to  be  referred  to  the  associated  extirpation  of  the  parathyroid 
bodies  imbedded  in  the  thymus  tissue. 

According  to  Ranzi  and  Tandler,  the  dentition  is  also  delayed  in  this  stage; 
the  dogs  take  on  abundant  fat  (stadium  adipositatis,  according  to  Klose  and 
Vogt).  This  is  followed  by  a  stadium  cachecticum;  in  spite  of  increased 
hunger  the  animals  gradually  lose  weight,  muscular  tremors  occur,  the  hemo- 
globin contents  and  erythrocyte  contents  of  the  blood  reduce,  and  chemotactic 
irritants,  such  for  examples,  injection  of  nucleinic  acid,  remain  inactive.  The 
animals  become  indolent  and  tired,  begin  to  suffer  with  disturl)ances  of  coordi- 
nation and  finally  die  in  a  coma-like  condition.  Feeding  with  thymus  gland 
or  injection  of  it  only  aggravates  the  condition. 


PATHOLOGY    AND    SEMIOLOGY  225 

H.  Matti  describes  the  condition  after  thymectomy  in  very  young  animals 
as  somewhat  different.  After  the  latent  period  of  about  four  weeks,  during 
which  the  animals  remain  behind  in  growth,  manifestations  occur  in  the  osse- 
ous system  that  are  very  much  like  those  of  high-grade  rachitis.  There  occur 
a  high-grade  softening  and  bowing  of  the  bones  and  a  rosary  formation;  there 
is  found  a  deficient  apposition  of  calcium  in  the  bones,  the  bone  marrow  is 
hyperemic  and  the  metaplasia  in  the  fat  marrow  is  slowed.  The  epiphysial 
junctures  are  several  times  broadened.  The  examination  of  the  blood  only 
shows  that  the  decrease  in  lymphocytes  which  normally  occurs  with  increas- 
ing age  and  the  increase  in  neutrophilic  elements  is  slowed.  Matti  found 
a  broadening  of  the  suprarenal  medulla  and  a  slight  enlargement  of  the 
thyroid  gland  and  of  the  pancreas.  The  gray  substance  of  the  spinal 
cord  shows,  as  Klose  and  Vogt  have  already  stated,  signs  of  an  increased 
breaking  up.  At  the  close  the  animals  lose  the  ability  to  walk  and  there 
ensues  marked  cachexia  that  leads  to  death.  The  muscles  show  high-grade 
atrophy  of  inactivity,  with  transitions  to  degenerative  atrophy. 

In  thymectomy  in  somewhat  older  animals  these  manifestations  occur 
only  temporarily,  yet  when  the  extirpation  was  associated  with  removal  of  the 
spleen,  the  animals,  according  to  Klose  and  Vogt^  for  the  most  part  died. 
This  would  signify  that  the  spleen  takes  over  at  least  a  part  of  the  function  of 
the  thymus  gland.     Matti  could  not  find  this. 

It  should  be  mentioned  further  that  castration  in  young  animals  essentially 
delays  the  involution  of  the  thymus  gland  and  that  increased  sexual  activity 
accelerates  it  {Calzolari,  Henderson,  N.  Paton,  and  Goddall,  and  others). 
With  this  agrees  the  fact  that  in  eunuchs,  Tandler  and  Grosz  found  the  thymus 
gland  hyperplastic. 

Svehla^s  experiments  on  hyper thymization  have  in  part  lost  their  signifi- 
cance, as  it  has  been  shown  by  Popper  that  the  depressor  action  of  thymus 
extracts  intravenously  is  not  specific,  but  is  dependent  on  clots  in  the  blood 
path. 

Pathology  and  Semiology. — Our  knowledge  as  to  the  significance  of  the 
thymus  gland  in  clinical  medicine  is  extremely  deficient.  As  far  as  symptoms 
in  the  absence  of  the  thyroid  gland  in  human  beings  is  concerned  we  know  next 
to  nothing. 

In  the  autopsy  of  new  born  and  very  small  children  aplasia  of  the  thymus 
gland  has  sometimes  been  found.  The  first  statement  is  that  of  Bischofif. 
Clark  described  an  eight-month-old  child  that  remained  well  up  to  the  sixth 
month.  Then  there  developed  hydropic  swellings.  Autopsy  showed  left- 
sided  hydronephrosis  and  aplasia  of  the  thyroid  gland,  v.  Sury  describes  a 
case  of  congenital  total  defect  of  the  thymus  gland  in  a  three-month-old  child 
who  died  of  pneumonia.  Aplasia  of  the  thymus  gland  seems  very  frequently 
to  be  associated  with  other  malformations,  especially  developmental  de- 
fects of  the  brain  (Winslow,  Borneville,  Katz,  and  others).  On  the  other 
IS 


2  26  THE    DISEASES    OF    THE    THYMUS    GLAXD 

hand,  G.  Anton  shows  the  simultaneous  occurrence  of  thymus  hyperplasia 
and  brain  hypertrophy. 

Lately  total  extirpation  of  the  thymus  gland  has  been  carried  out  on 
account  of  stenosis  of  the  trachea  (see  below).  Very  worthy  of  note  is  the 
statement  of  Koenig,  that  after  resection  of  the  thymus  gland  such  as  w^as 
undertaken  in  a  nine-month-old  child  on  account  of  dyspnea,  breathing  be- 
came normal  and  afterwards  a  severe  rachitis  developed  on  account  of 
which  the  child  first  learned  to  walk  as  late  as  the  age  of  four  and  one-half 
years.  In  the  rest  of  the  cases  there  are  no  statements  as  to  the  further  course. 
According  to  the  experiences  in  animals,  tlje  experiments  up  to  the  present, 
total  extirpation  of  the  thymus  gland  in  very  young  children  is  to  be  advised 
against. 

Up  to  the  present  the  entire  clinical  interest  has  been  turned  to  the  cases 
which  have  shown  a  hyperplasia  of  the  thymus  gland  and  a  persistence  or 
reviviscence  of  the  same.^  Kopp  in  1855  first  attracted  the  interest  of 
the  medical  world  to  the  cases  of  sudden  death  in  early  life  which  occurred 
with  cyanosis  and  stridor  and  which  on  section  showed  nothing  but  hyper- 
plastic thymus  gland.  The  extensive  investigations  of  Friedleben,  which 
culminated  in  the  aphorism  ''  there  exists  no  thymic  asthma,"  for  a  long  time 
suppressed  this  teaching.  First  in  the  year  1888  Grawitz  on  the  evidence  of 
two  tases  pointed  out  the  forensic  significance  of  thymic  hyperplasia.  Up  to 
this  time  only  purely  mechanical  factors  in  these  cases  of  death  had  been  con- 
sidered. Then,  in  1889,  A.  Paltauf,  finding  out  the  frequent  combination  of 
thymic  hyperplasia,  status  lymphaticus,  and  narrowing  of  the  vascular  system 
regarded  the  cause  of  death  not  as  a  mechanical  factor  but  as  a  vegetative  dis- 
turbance which  he  designated  as  lymphato-chlorotic  constitution.  Among 
others,  Ortner  reported  congenital  narro\\'ing  of  the  aortic  system  in  these  cases 
of  sudden  death,  v.  Kundrat  status  lymphaticus  with  more  or  less  large  thy- 
mus gland  in  cases  of  sudden  death  in  narcosis,  Schnitzler  and  others  narcotic 
death  in  cases  of  Basedow's  disease  with  persistence  of  the  thymus  and  status 
lymphaticus.  With  Pott  originated  an  excellent  description  of  the  cases  of 
sudden  death  in  the  years  of  childhood.  ]\Iost  authors  agree  with  the 
view  of  A.  Paltauf,  in  that  they  regard  the  mechanical  factor  as  without  sig- 
nificance and  place  in  the  foreground  the  lability  of  the  organism  or  the 
cardio-vascular  system  that  is  dependent  on  toxic  factors.  Especially  in- 
teresting are  the  observations  of  the  familial  occurrence  of  these  species  of 
sudden  death  {Perrin,  Hedinger,  and  others).  Certain  authors,  however, 
hold  fast  to  the  mechanical  cause  through  compression  of  the  trachea  by  the 
thymus  gland. 

^  Persistence  of  the  thymus  gland  is,  properly  speaking,  an  incorrect  expression  as  every 
human  being  possesses  a  thymus  gland  for  his  whole  lifetime.  Better  than  "persistence"  is 
higher  parenchj'mal  value  than  corresponds  to  the  age;  also  a  reviviscence  is  really  not  certain, 
as  we  do  not  possess  a  criterion  for  it. 


PATHOLOGY   AND    SEMIOLOGY  227 

The  question  is  not  completely  cleared  up  at  the  present  day  although  the 
direction  in  which  we  may  expect  the  clearing  is  indicated.  What  makes  the 
question  especially  difficult  is  the  circumstance  that  status  lymphaticus  and 
enlarged  thymus  gland  occur  so  frequently  in  associationship.  Apparently, 
however,  they  stand  to  each  other  in  a  conditioned  relation.  As  we  shall  see 
later  in  another  paragraph,  the  finding  of  an  intumescence  of  the  lymphatic 
apparatus  eventually  with  a  mononucleosis  in  the  blood  is  very  frequent  in- 
deed. We  find  this  in  numerous  diseases  of  the  ductless  glands,  in  chronic 
infectious  diseases,  in  neurosis  of  the  vagus  nerve,  etc.  These  hyperplasias 
deviate  markedly  from  one  another  histologically.  In  addition,  it  is  per- 
fectly clear  that  not  every  chronic  swelHng  of  the  lymphatic  apparatus  is 
associated  with  increased  chemic  function.  Also  the  thymic  hyperplasia  or 
thymic  persistence  or  reviviscence  is  extraordinarily  frequent  just  in  these 
diseases  of  the  ductless  glands.  If  we  accept  the  view  that  the  thymus 
gland  is  in  part  of  mesodermal  origin,  therefore  in  part  belongs  to  the  lym- 
phatic apparatus,  this  frequent  combination  of  enlarged  thymus  gland  and 
status  lymphaticus  would  not  be  inexplicable.  There  certainly  exists, 
however,  an  abnormally  large  thymus  gland  without  status  lymphaticus, 
hence  a  status  thymicus. 

Recent  investigations  seem  to  have  furnished  a  significant  dift'erentiating 
criterion.  Wiesel  and  Eedinger  have  shown  that  status  lymphaticus  is  asso- 
ciated with  a  hyperplasia  of  the  chromaffin  tissue.  Thus  Hedinger  found  in 
five  cases  of  pure  thymic  hyperplasia  entirely  normal  development  of  the 
suprarenals  and  the  entire  chromaffin  tissue,  also  on  microscopical  exami- 
nation. Again,  v.  Sury  points  out  that  in  the  so-called  thymic  death  of  the 
new-born  the  chromaffin  tissue  is  always  well  developed  and  that  the  hypo- 
plasia of  the  chromaffin  tissue  sets  in  only  with  the  development  of  status 
lymphaticus.  In  cases  of  pure  thymus  hyperplasia  the  lymphocytosis  of  the 
blood  would  seem  to  be  absent.^ 

Let  us  now  turn  again  to  the  question  of  thymic  death,  v.  Siiry  has 
treated  this  subject  in  an  elucidative  exposition,  one  especially  adequate  on 
account  of  its  rigid  critique.  He  bases  his  conclusions  on  the  material  of  two 
hundred  medicolegal  autopsies  in  which  the  thymus  gland  was  taken  into 
account,  v.  Sury  shows  first  that  the  thymus  gland  varies  extraordinarily 
in  size  and  that  therefore  the  diagnosis  of  a  thymus  hyperplasia  is  often  very 
arbitrary.  He  mentions  further  that  in  the  cases  of  sudden  death  in  children 
apparently  healthy  beforehand  there  exists  very  frequently  capillary  bronchi- 
tides  which  are  very  common  and  which  are  very  easily  overlooked.  In  spite 
of  this  we  can  hardly  deny  the  significance  of  the  mechanical  factor  in  the 
cases  of  ^^ thymic  asthma^'  published  in  recent  years — cases  which  after  partial 

^  Often  in  pure  status  thymicus  the  epithelial  thymic  tissue,  that  is,  the  reticulum  and  its 
derivatives,  is  found  hj'perplastic  while  the  small  thymic  cells  do  not  necessarily  have  to  be  in- 
creased, in  contrast  with  status  lymphaticus  {Wiesel). 


2  28  THE    DISEASES    OF    THE    THYMUS    GLAXD 

or  complete  extirpation  of  the  thymus  gland  became  greatly  relieved  of  their 
oppressive  symptoms.  Klose  and  Vogi  have  collected  eight  such  cases.  The 
first  case  was  operated  on  by  Rehn  (reported  by  Parucker) .  It  was  that  of  a 
two-and-a-half-year-old  child.  Since  that  time  a  series  of  other  cases  have 
been  operated  on  (see  the  literature  in  Wiesel).  Especially  to  be  mentioned 
is  the  case  of  HinricJis  in  which  the  hyperplastic  thymus  gland  led,  in  addition 
to  a  hindrance  of  breathing,  to  a  high-grade  disturbance  of  the  ingestion  of 
food.  Lately  the  action  of  the  X-rays  has  also  been  recommended  {Fried- 
lander,  Myers,  RacJiford,  Rihidcaii  and  Weil).  The  case  of  Rihideau  was  that 
of  a  two-month-old  child  with  marked  need  for  air  on  account  of  h}'perplasia 
of  the  thymus.  After  extensive  irradiation  with  X-rays  the  dyspneic  mani- 
festations disappeared  within  two  days;  somewhat  later  the  child  died 
from  measles.     The  autopsy  showed  fibrous  atrophy  of  the  thymus  gland. 

The  attacks  of  dyspnea,  cyanosis,  stridor,  and  eventually  hoarseness,  that 
were  observed  in  all  these  cases  speak  indeed  for  a  purely  mechanical  factor. 
Whether  in  the  pure  cases  of  status  thymicus  in  addition  to  this  mechanical 
factor  there  exists  a  toxic  factor  on  account  of  hyperthymization  we  must  for 
the  present  leave  undecided;  although  I  have  hardly  been  able  to  discover  any 
grounds  for  this  assumption.  Up  to  the  present  the  cases  of  Basedow's  dis- 
ease in  which  death  occurred  suddenly  in  narcosis  regularly  showed  in  ad- 
dition to  thymus  hyperplasia  a  pronounced  status  lymphaticus  and  were  in 
addition  complicated  by  other  factors. 

It  should  be  mentioned  further  that  the  thymus  gland  can  also  be  the  seat 
of  malignant  tumors  or  of  inflammatory  processes.  The  numerous  thymic 
tumors  thus  far  observed  have  not  furnished  any  information  as  to  the  physi- 
ology of  the  gland,  v.  Xeusscr  described  a  case  of  sarcoma  of  the  thymus 
gland;  a  twenty-fiA'e-year-old  patient  was  remarkably  large  and  showed  hy- 
perplasia of  the  genitaha.  A  short  time  ago  we  observed  a  case  of  carcinoma; 
here  also  there  existed  gigantism;  the  development  of  the  genitaha 
was,  however,  entirely  normal.  There  should  also  be  mentioned  the  case  of 
Bramwell  in  which  was  found,  in  addition  to  the  sarcoma  of  the  suprarenal 
gland,  a  carcinoma  of  the  thymus.  Finally  in  numerous,  but  not  all,  cases  of 
myasthenia  gravis  there  were  found  liN-perplasia  of  the  thymus  gland  and 
alterations  in  the  muscles  that  were  regarded  as  lymphosarcoma.  This  in- 
terpretation is  not  however  certain,  as  liassaVs  corpuscles  occur  in  the 
muscle  metastases.  In  these  cases  we  are  dealing  rather  with  reticulum 
tumors. 

If  our  trying  to  draw  a  resume  out  of  the  facts  detailed,  we  find  that  it 
cannot  be  denied  that  in  spite  of  the  enormous  labor  that  up  to  the  present 
has  been  spent  on  this  subject,  the  physiological  significance  of  the  thymus 
gland  is  still  unclear.  The  destruction  of  the  organ  through  tumors  or  in- 
flammatory processes  which  have  otherwise  furnished  us  with  so  much  im- 
portant information  in  the  pathology  of  the  other  ductless  glands  is  here 


ADDENDUM  229 

apparently  entirely  without  significance.  Operative  extirpations  of  the  gland 
in  earliest  childhood  have,  except  in  the  single  case  of  Komg  previously 
mentioned,  furnished  no  symptoms  of  absence.  However,  we  should  not  for- 
get that  we  mostly  deal  with  cases  of  resections  and  that  also  in  most  of  the 
cases  statements  as  to  the  further  course  are  absent.  Then  again  we  must 
consider  the  presence  in  such  cases  of  accessory  lobules  of  the  thymus. 

Just  as  little  clarified  appears  to  me  the  significance  of  thymic  hyper- 
plasia for  pathology.  In  many  cases  only  the  significance  of  the  mechanical 
factors  remain  certain;  this  is  however  quite  without  significance  for  the  ques- 
tion of  hyperthymization.  For  the  rest  we  really  only  know  that  in  a  great 
number  of  very  diverse  conditions  we  find  thymus  glands  with  supernormal 
parenchymal  values.  Especially  is  this  true  for  diseases  of  the  ductless 
glands.  We  find  thymus  hyperplasia  very  frequently  in  Basedow's  disease, 
apparently  also  in  acromegaly,  in  hypophysial  dystrophy,  in  myxedema,  in 
eunuchoidism,  etc.  It  therefore  occurs  as  well  in  conditions  of  glandular  hyper- 
function  as  in  hypofunction.  I  believe,  therefore,  that  we  should  exercise 
great  scepticism  concerning  theories  that  would  explain  the  frequent 
coincidence  of  Basedow's  disease  and  thymic  hyperplasia.  On  the  same 
ground  I  regard  as  at  present  quite  hypothetical  the  correlations  that 
according  to  the  views  of  many  modern  authors  exist  between  the  thymus 
gland  and  the  other  glands  of  internal  secretion. 

Also  the  experiments  to  produce  hyperthymization  artificially  have  up  to 
the  present  seemed  scarcely  satisfactory.  The  old  experiments  of  Svehla  are, 
as  has  already  been  mentioned,  not  of  value  as  evidence.  The  fewer  ex- 
periments of  Hart  with  injection  of  powdered  Basedow's  thymus  and  those 
of  Bircher  with  implantation  of  Basedow's  thymus  in  animals  are  worthy  of 
notice  but  do  not  furnish  sufficient  grounds  for  the  support  of  a  teaching  of 
hyperthymization.^  Also  the  hypothesis  that  Wiesel  provides  at  the  end 
of  his  unusually  well-prepared  work  on  the  pathology  of  the  thymus  seems  to 
me  on  the  face  of  it  as  still  too  little  supported.  Wiesel  supposes  that  the 
thymus  gland  furnishes  to  the  blood  path  a  secretion  that  acts  vagotonically, 
and  he  regards  especially  the  eosinophilic  cells  present  so  abundantly  in  the 
thymus  gland  as  the  seat  of  origin  of  this  principle  that  acts  antagonistically 
to  adrenalin.  In  this  respect  Wiesel  identifies  status  thymicus  and  status 
lymphaticus,  although  he  does  take  pains  to  separate  the  two  conditions 
from  each  other  in  an  anatomical  sense. 

Addendum 

Boggs  points  out,  without  regards  to  the  dulness  due  to  enlarged  thymus 
is  partially  higher  and  more  superficial  than  that  due  to  diseased  mediastinal 

^Concerning  the  " thymogenic "  Basedow's  disease  see  chapter  on  thyroid  gland,  pp.   75 
and  90. 


230  THE    DISEASES    OF    THE    THYMUS    GLAND 

lymph  glands  or  other  forms  of  mediastinitis;  that  it  is  constantly  much  more 
marked  on  the  left  of  the  sternum  than  the  right,  and  the  dulness  is  movable, 
the  lower  border  rising  as  much  as  an  interspace  when  the  head  is  shifted  from 
extreme  flexion  to  extreme  extension,  with  the  patient  in  the  sitting  position. 
"In  some  cases  of  persistent  or  enlarged  thymus  there  may  be  no  dulness  in 
the  first  interspace,  but  only  in  the  second  and  below  it.  In  such  instances  a 
shift  in  both  upper  and  lower  borders  of  dulness  may  be  made  out." 

The  movement  in  the  dulness  of  the  thymus  is  explained  by  this  author  as 
due  to  the  movability  of  the  thymus  itself.  He  found  the  thymus  to  be  en- 
larged or  persistent  in  thirty-five  of  sixty-six  colored  girls,  between  the  ages 
of  five  and  eighteen  years,  fourteen  of  whom  had  suffered  from  measles. 
He  remarked  that  lymphatic  hyperplasia  seems  more  common  in  the  colored 
race.  Jacobi,  in  the  discussion  on  Bogg's  article,  recommends  percussing 
with  the  child  in  the  prone  position. 

Park  and  McGuire,  however,  on  the  basis  of  twenty-nine  autopsies,  have 
determined  that  the  thymus  gland  is  a  relatively  immobile  organ  and  that 
the  methods  of  percussion  used  by  Jacobi  and  by  Boggs  bring  out  a  movable 
dulness  that  is  due  to  other  factors,  probably  to  the  upward  advance  of  the 
lung  margins. 

Of  recent  cases  of  apparent  thymic  death,  it  is  probable  that  death  in  the 
cases  of  Ginsburg  and  of  Kennedy  was  due  to  mechanical  factors,  while  in 
Veeder's  case,  it  is  not  at  all  certain  that  the  thymus  had  anything  to  do  in 
the  matter. 

In  a  recent  review%  Rickells  mentions  the  various  surgical  procedures  on 
the  thymus  gland,  and  points  out  that  in  case  of  impending  suffocation  due  to 
enlarged  thymus,  intubation  or  tracheotomy  may  be  done. 

According  to  Halsted,  Klose  warns  against  X-ray  irradiation  of  the 
thymus  region  in  young  children,  because  of  the  marked  susceptibility  of  the 
gland  to  the  influence  of  the  X-ray. 

References 

Bo^gs  (T.  R.).  Percussion  signs  of  persistent  or  enlarged  thymus.  Tr.  .A.ss.  Am. 
Phys.,  Vol.  XXVI,  191 1,  pp.  353-356- 

Park  {E.  A.)  and  McGuire  (W.  C).  A  criticism  of  two  percussion  methods  for  the 
diagnosis  of  enlarged  thymus.     Arch.  Int.  Med.,  Vol.  X,  No.  3,  Sept.,  191 2,  pp.  214-218. 

Ginsburg  (N.).  Thoracic  viscera  in  a  case  of  thymic  enlargement.  Proc.  Path. 
Soc.  Phila.,  N.  S.,  Vol.  XIV,  1911,  p.  82. 

Kennedy  (.1.  M.).  Enlargement  of  the  thymus;  a  remarkable  case.  Glasgow  M. 
J.,  Vol.  XXVII,  Jan.,  1912,  pp.  31-37. 

Veeder  {B.  S.).  Hemorrhage  into  the  parathyroid  glands  in  a  case  of  "thymic  death." 
Proc.  Path.  Soc.  Phila.,  N.  S.,  Vol.  XIV,  191 1,  p.  83. 

Halsled  [W.  S.).  The  significance  of  the  thymus  gland  in  Graves'  disease.  Bulletin 
of  the  Johns  Hopkins  Hospital,  Vol.  XXV,  N^o.  282,  Aug.,  1914,  PP-  223-228. 


CHAPTER  VI 
THE  DISEASES  OF  THE  HYPOPHYSIS  [PITUITARY  GLAND] 

Since  Pierre  Marie  delineated  the  clinical  picture  of  acromegaly  and 
placed  it  in  an  etiological  relationship  to  the  hypophysis,  the  literature  on 
the  experimental  research  and  clinical  study  of  the  hypophysis  has  grown 
enormously.  In  spite  of  this  fact  there  as  yet  prevails  in  our  views  as  to  the 
pathogenesis  of  the  clinical  pictures  concerned  with,  the  hypophysis  very 
little  uniformity.  The  chiefest  cause  of  this  is  that  as  yet  we  knOw  but  little 
as  to  this  organ's  physiological  significance,  at  least  much  less  than  we  know 
about  the  thyroid.  The  blame  resides  principally  in  the  difhcult  accessibility 
of  the  gland  for  experimental  purposes,  and  further  the  fact  that  here  we 
have  to  do  with  two  organs  intimately  bound  together  and  enclosed  in  a  rigid 
bony  cavity.  A  certain  physiological  independence  of  these  two  organs  might 
be  expected  from  their  morphological  and  embryological  independence. 
Hence  we  may  speak  of  a  hypophysial  apparatus  showing  certain  analogies 
with  the  thyroid  apparatus  (thyroid  gland  and  parathyroid  glands)  and  with 
the  corresponding  suprarenal  apparatus  (cortex  and  chromaffin  medulla), 
hereafter  to  be  described.  The  differentiation  of  the  pathological  mani- 
festations accruing  to  the  two  systems  is  made  more  difficult  than  that  of  the 
pathological  manifestations  affecting  the  other  ductless  gland  groups  because 
on  account  of  the  enclosure  in  a  rigid  cavity  an  affection  of  one  of  the  organs 
seldom  leaves  the  other  entirely  uninvolved. 

In  an  attempt  to  delimit  and  to  explain  the  clinical  pictures  presented 
by  the  hypophysial  apparatus  the  following  four  points  seem  to  begin  to  be 
important,  i.  The  characteristic  typographical  relations,  2.  the  embryo- 
logical  development,  3.  a  certain  physiological  independence,  and  4.  the  mani- 
fold analogies  that  exist  between  the  glandular  hypophysis  and  the  thyroid 
gland. 

Anatomy  and  Embryology. — The  normal  hypophysis  of  man  weighs  on 
the  average  somewhat  more  than  0.5  gm.  It  consists  in  a  glandular  anterior 
lobe  and  a  nervous  posterior  lobe.  Both  lie  in  the  sella  turcica,  into  which 
cavity  the  dura  penetrates  through  the  foramen  sellae  turcicae  and  surrounds 
them  both  in  common.  From  the  anterior  lobe  a  small  process  projects 
forward  in  the  so-called  peduncle  of  the  hypophysis  while  the  posterior  lobe 
is  directly  in  communication  with  the  brain  by  means  of  the  infundibulum. 
A  tapering  cleft,  the  recessus  infundibuli,  in  communication  with  the  third 
ventricle,  penetrates  deeply  into  the  peduncle. 

The    following    scheme    after    Erdheim    shows    these    relations:     Ch.  = 

231 


232 


THE    DISEASES    OF    THE    HYPOPHYSIS 


chiasm;    V.L.  =  anterior    lobe;    H.L.  =  posterior    lobe;    Pl.efi.  =  accumu- 
lations of  squamous  epithelium;  R.C.  =  Rathke's  cyst;  F  =  process;  E  = 

terminal  enlargement  of  process;  r.i. 
=  recessus  infundibuli;  /.  =  infun- 
dibulum;  D.  —  dura;  D-i  =  dia- 
phragma  sellae;  A.  =  arachnoid. 

The  anterior  lobe  is  supplied  by 
small  branches  of  the  internal  car- 
otid artery,  the  posterior  lobe  by  ves- 
sels of  the  pia.     The  veins  end  in  the 
sinus    circulosus    Ridleyi.     Anterior 
and  posterior  lobes  are  surrounded 
by  a  capsule  of  the  dura  mater,  which 
capsule   overhangs   the   entrance   to 
the  sellae  in  the  form  of  a  diaphragm 
that  is  perforated  by  the  infundibular 
peduncle. 
The  anterior  lobe  for  the  most  part  consists  in  epithelial  columns.     Here 
are  found  chromophilic  cells  in  which  Benda  by  the  employment  of  a  specific 
stain  has  demonstrated  eosinophilic  and  basophilic  granules.     Here  are  also 


Jv. 


R.C. 


D. 


Fig.  30. — Diagram  of  the  structure  of  the  hy 
pophysis  (after  Erdheim). 


•^ 


|0   4^  ® 


c.  c. 


B.C. 


E.  C. 


^ 


Fig.  31. — Anterior  lobe  of  the  hypophysis.    E.C.  =  eosinophile  cells.    B.C.  =  basophile  cells. 

C.C.  =  chief  cells. 


ANATOMY  AND  EMBRYOLOGY 


233 


found  cells  that  are  nongranular:  the  so-called  principal  cells,  which  during 
pregnancy,  according  to  Erdheim  and  Stumme,  develop  into  the  so-called 
pregnancy  cells. 

Posteriorly  the  anterior  lobe  is  delimited  from  the  so-called  pars  inter- 
media by  a  poorly  vascularized  layer  of  connective  tissue.  The  especial 
histological  character  of  the  pars  intermedia  has  been  emphasized  by  Her- 
ring. Here  are  found  follicle-like  pictures  filled  with  colloid.  This  cellular 
layer  has  also  been  called  the  cork  layer  or  Peremeschko's  medullary  layer. 
Here  lies  also  the  so-called  Rathke's  cyst. 

The  posterior  lobe  is  made  up  of  glial  tissue 
and  scattered  cells,  the  character  of  which  has 
not  as  yet  been  established,  and  of  nerve  fibers. 

The  hypophysis  of  man  undergoes  character- 
istic alterations  during  pregnancy.  First  Comte, 
in  six  pregnant  women,  found  enlargement  of 
the  hypophysis  and  multiplication  of  all  the  sorts 
of  cells.  Later  Erdheim  and  Stumme  made  a 
careful  study  of  the  alterations.  According  to 
both  these  authors  the  enlargements  affect  only 
the  anterior  lobe.  The  differences  in  size  are 
very  appreciable.  While  the  weight  of  the 
hypophysis  in  a  nullipara  is  about  61.8  cgm. 
on  the  average,  Erdheim  and  Stumme  found  it 
to  be  on  the  average  84.7  cgm.  in  primiparse 
and  106  cgm.  in  multiparas. 

Through  its  position  the  hypophysis  shows 
special  relations  to  the  chiasm  of  the  optic 
nerves  and  to  the  third  and  sixth  cranial  nerves. 

The  emhryological  development  of  the  hypo- 
physial apparatus  is  shown  in  the  following 
three  sketches,  which  are  taken  from  the  works 
of  Erdheim  and  of  Mihalkovic. 


Fig. 


32- 


-Development 

hypophysis. 


of    the 


i  =  infundibulum. 

h  =  Rathke's  pouch. 

X  =  boundary  between  epithelium  originating  from  the  primary 

ectodermal  oral  diverticulum  and  the  entodermal  head-gut. 
Pi  =  solid  process  (anterior  lobe) . 
g  =  hypophysial  duct. 

X  =  original  insertion  of  the  hypophysial  duct. 

pi  =  process  of  the  grown-out  [ausgewachsen]   normal  hypophysis. 
X  =  collection  of  accumulations  of  squamous  epithelium,  probably 

remnants  of  the  hypophysial  duct  originating  from  the  epi- 


234  THE    DISEASES    OF    THE    HYPOPHYSIS 

thelium  of  the  oral  diverticulum,  while  the  epithelium  of  the 
hypophysial  duct  is  cubical. 

The  nervous  lobe  of  the  hypophysis  originates  from  the  diencephalon. 
Here  there  develops  a  pouch-like  protrusion  (processus  infundibularis),  which 
during  the  fourth  week  adjoins  a  similar  pouch  originating  from  the  epithe- 
lium of  the  oral  diverticulum  {Rathke's  hypophysial  pouch).  In  the  lower 
classes  of  animals  there  exists  an  intimate  spatial  relationship  between  the 
two,  due  to  the  fact  that  the  infundibular  peduncle,  which  in  these  animals 
is  much  better  developed,  is  overlain  in  a  cup-like  manner  by  the  epithelial 
part  (see  Edinger,  Bau  der  nervosen  Zentralorgane  des  ]\Ienschen  und  der 
Tiere,  2,  Bd.  7  Edition,  1908).  In  man  this  intimate  relationship  between 
anterior  and  posterior  lobes  is  by  no  means  so  extensive.  Here  principally 
the  posterior  lobe  is  very  much  less  well  developed. 

The  question  as  to  whether  the  pars  intermedia  belongs  to  the  anterior 
or  to  the  posterior  lobe  seems  to  me,  according  to  what  I  can  find  in  the 
literature  as  to  this  subject,  as  yet  not  cleared  up.  At  all  events  the  facts 
are  important  that  on  separation  of  the  anterior  lobe  from  the  posterior  the 
pars  intermedia  always  remains  with  the  posterior — a  fact  also  mentioned 
by  Cushing — and  that,  as  had  already  been  mentioned,  the  anterior  lobe  and 
the  pars  intermedia  are  always  separated  by  a  layer  of  connective  tissue. 
This  question  seems  to  me  to  be  a  very  important  one  from  the  clinical 
standpoint.  As  is  known,  the  posterior  lobe  and  the  pars  intermedia  contain 
a  substance  that  increases  blood-pressure  and  acts  as  a  diuretic,  a  substance 
that  in  its  action  shows  a  certain  similarity  to  adrenalin.  It  is,  therefore,  not 
impossible  that  the  pars  intermedia  possesses  in  its  relation  to  the  nervous 
system  similar  embryological  relations  to  those  which  have  been  demon- 
strated for  the  chromafRn  tissue. 

The  analogy  in  the  development  of  the  glandular  lobe  of  the  hypophysis 
with  that  of  the  development  of  the  thyroid  is  apparent.  Both  originally  are 
glands  with  external  secretion.  Just  as  is  the  case  with  the  hypophysial 
duct,  the  ductus  thyreoglossus  undergoes  atrophy;  this  also  leaves  behind  cell 
accumulations  which  consist  chiefly  of  stratified  plaster  epithelium.  Accord- 
ing to  the  recent  investigations  of  Haberfdd  the  hypophysial  duct  may,  espe- 
cially when  there  are  malformations  of  the  skull,  persist.  This  has  also  been 
observed  in  acromegaly  (Ettore  Levi).  It  is  of  especial  significance  for  the 
pathogenesis  of  acromegaly,  as  we  shall  see  later,  that  accumulations  of 
typical  glandular  epithelium  may  be  found  on  the  roof  of  the  pharynx  as  well 
as  along  the  persistent  craniopharyngeal  canal,  from  which  accumulations 
may  be  formed  adenomata. 

The  glandular  anterior  lobe  of  the  hypophysis  is  a  true  ductless  gland. 
The  opinion  has  been  expressed  that  its  secretion  streams  off  through  the 
posterior  lobe.     Against  this  speaks  first  the  separate  blood  supplies,  then 


ACROMEGALY  235 

the  fact  that  the  posterior  lobe  may  be  removed  without  the  anterior  lobe's 
losing  its  function  {Crowe,  Gushing  and  Homans),  and  finally  the  observation 
of  V.  Cyon  that  in  hypophyses  of  cattle  and  sheep  the  anterior  and  posterior 
lobes  may  be  separated  from  each  other  by  small  plates  of  bone.  It  may  well 
be  supposed  that,  as  is  true  for  the  external  secretion  of  the  thyroid,  the  exit 
channel  for  the  internal  secretion  of  the  anterior  lobe  is  formed  by  the  lymph- 
vessels  or  the  blood-vessels. 

The  secretion  of  the  posterior  lobe  would  seem  to  pour  out  into  the  third 
ventricle  through  the  recessus  infundibuli.  Cushing  and  Gotscli  in  animal 
experiments  found  that  the  cerebrospinal  fluid  increases  the  blood-pressure 
in  a  manner  analogous  to  the  action  of  infundibular  extract.  I  would  like 
to  see  demonstrated  the  fact  that  the  cerebrospinal  fluid  acts  as  a  diuretic  as 
does  pituitrinum  infundibulare. 

a.  Acromegaly 
Hyperpituitarism,  Marie's  Disease 

Definition. — By  acromegaly  we  understand  a  disease  that  is  characterized  by 
the  gradual  enlargement  of  the  peaked  [gipf elude,  i.e.,  peaked,  acral]  parts  {nose, 
lips,  tongue,  lower  jaw,  hands  and  feet)  and  by  hyperplastic  alterations  in  the 
entire  osseous  system.  There  mostly  develops  an  appreciable  enlargement  of  the 
hypophysis,  which  leads  to  broadening  of  the  sella  turcica.  Associated  with  this 
is  localization  of  corresponding  symptoms  of  brain  pressure.  To  this  are 
added  very  frequently  alterations  of  the  thyroid  gland  of  a  hyperplastic  character, 
marked  accentuation  of  the  function  of  the  interstitial  glands;  also,  very  frequently, 
loss  of  function  of  the  genital  glands  after  preliminary  transitory  increase  of 
fimction,  and,  apparently  frequently,  hyperplasia  of  the  suprarenal  cortex. 
Also  the  condition  of  excitability  of  the  vegetative  nerves  is  sometimes  increased 
in  manifold  ways.  Very  frequently  there  occurs  rapid  withering  away  of  the 
body  and  manifestations  of  degeneration  of  manifold  nature.  The  pathological 
anatomical  finding  in  the  hypophysis  is  an  adenoma  or  adenocarcinoma  of 
the  anterior  lobe.  To-day  we  refer  acromegaly  to  an  increase  of  function  of  the 
glandular  hypophysis. 

Occurrence. — Acromegaly  is  not  a  very  rare  disease.  It  does  not  seem  to 
give  preference  to  any  country  or  to  any  race  of  people.  It  usually  begins 
between  the  ages  of  twenty  and  forty  years,  most  frequently  between 
the  twentieth  and  thirtieth  year  of  Hfe  {Sternburg) .  According  to  this  author 
it  usually  occurs  in  women  later  than  in  men.  There  are  also  rare  cases 
of  acromegaly  that  begin  in  the  years  of  childhood  or  adolescence.  These 
are  of  special  importance.  I  shall  refer  to  them  in  greater  detail  in  the 
consideration  of  the  pathogenesis.  Hereditary  or  familial  occurrence 
seems  to  be  very  rare.  I  have  found  very  few  statements  as  to  this  ques- 
tion in  the  literature  and  all  these  are  verv  indefinite.     Thus  Arnold  in 


236  THE    DISEASES    OF    THE    HYPOPHYSIS 

1891  described  in  detail  a  case  of  acromegaly  that  began  in  the  eighteenth 
year  of  life.  One  of  the  patient's  brothers  was  affected  with  the  same 
disease  earlier  in  Hfe.  Also  Frdnizel  describes  a  case  in  which  the  affec- 
tion began  in  boyhood;  in  the  eleven-year-old  daughter  of  which  patient 
the  disease  was  also  recognizable.  In  this  family  were  many  indi\'iduals 
who  were  very  tall.  We  find  a  statement  of  Sclrwouer's  that  the  mother 
of  the  female  patient  who  was  seventy-three  years  old  apparently  be- 
came sick  with  acromegaly  at  the  age  of  fifty;  the  father  of  the  patient 
was  also  very  large.  Frdnkel,  Stadelmann  and  Benda  state  that  the  father 
of  two  blood  relations  of  the  case  described  by  them  was  said  to  have  shown 
the  same  anomaly.  In  the  case  reported  by  H.  Salomon,  we  find  the  state- 
ment that  the  mother  of  the  patient  seems  to  have  suft"ered  with  acromegaly 
and  diabetes. 

Symptomatology. — I  begin  with  a  description  of  the  alterations  in  the 
bones  and  soft  parts.  The  alteration  of  the  face  in  fully  developed  cases  can 
be  so  marked  that  the  individuals  actually  become  unrecognizable.  The  nose 
is  monstrously  thickened,  the  superciliary  arches  and  malar  bones  protrude 
markedly;  this  is  chiefly  dependent  on  an  increase  in  volume  of  the  pneu- 
matic cavities.  I  refer  to  the  X-ray  illustration  of  Observation  XXV  in 
which  the  large  frontal  cavity  is  to  be  seen  as  a  light  space.  Such  an  enlarge- 
ment may  bring  about  narrowing  of  the  auditory  passages  and  of  the  orbits. 
In  the  case  of  youthful  acromegaly  described  by  SchuUze  and  Fischer  there 
occurred  almost  complete  deafness  probably  due  to  the  thickening  of  the 
internal  ear.  Also  the  cranial  skull  may  increase  essentially  in  circumference, 
so  that  the  hats  no  longer  fit.  The  sutures  often  close  prematurely.  The 
external  occipital  protuberance  is  in  most  cases  enormously  developed.  The 
narrowing  of  the  orbits  may  bring  about  exophthalmus  although  this  may  be 
also  brought  about  by  other  causes  such  as  enlargements  of  the  eye-balls  and 
stagnation  in  the  cavernous  sinuses  {Benda) .  In  many  of  the  cases  associated 
with  symptoms  of  Basedow's  disease  the  cause  of  an  existing  exophthalmus 
may  be  due  also  to  a  heightened  tonus  of  Milller -Land stromas  muscle.  The 
great  variation  that  the  exophthalmus  shows  in  such  cases  may  be  as  well 
explained  in  this  manner  as  by  the  cause  assigned  by  Benda. 

Very  characteristic  is  the  spreading  apart  of  the  teeth  on  account  of  the 
enlargement  of  the  upper  jaw,  especially  of  the  lower  jaw.  On  account  of  the 
marked  prognathia  of  the  lower  jaw,  and  on  account  of  the  oblique  position 
of  the  alveolar  process  due  to  this,  chewing  becomes  almost  impossible.  The 
mucous  membrane  of  the  oral  cavity  is  for  the  most  part  thickened,  the 
tongue  can  so  increase  in  size  that  in  spite  of  the  enlargement  of  the  jaws  it 
projects  over  the  teeth.  The  mucous  mem])rane  of  the  tongue  becomes  thick- 
ened, the  papilhc  are  enlarged,  the  microscopic  examination  showed  enormous 
proHferation  of  the  interstitial  tissue,  while  the  muscle  fibers  show,  at  least  in 
the  later  stages,  signs  of  atrophy  and  degeneration.     On  account  of  the  thick- 


ACROMEGALY  237 

ening  and  the  weight  of  the  tongue  articulation  may  be  affected.  The  larynx 
is  often  considerably  enlarged,  the  voice  is  deep  and,  on  account  of  the  reson- 
ance in  the  enlarged  pneumatic  spaces,  abnormally  loud.  This  is  true  for 
both  male  and  female  individuals.  The  clavicles,  especially,  are  enlarged. 
Often  there  develops  rather  quickly  a  pronounced  kyphosis  of  the  lower  cer- 
vical and  upper  thoracic  spine  and  a  lordosis  of  the  lumbar  spine. 

Then,  too,  there  may  occur  ankylosis  of  the  vertebral  bodies.  The  ribs  are 
thickened  and  broadened.  Very  characteristic  is  the  tremendous  thickening 
of  the  places  for  the  insertion  of  the  muscles,  the  widening  of  the  vascular  for- 
amina and  the  deepening  of  the  vascular  furrows  {Sternberg);  the  entire 
osseous  system  can  be  enlarged  in  all  dimensions  as  in  the  cases  of  Schulize 
and  Fischer. 

On  the  hands  only  the  soft  parts  are  considerably  thickened,  the  thicken- 
ing occasioning  a  spreading  apart  of  the  metacarpal  bones.  The  hands 
become  paw-like.  The  X-ray  picture  does  not  show  anything  especially 
beyond  a  slight  thickening  of  the  places  of  muscular  insertion  (type  en  large, 
Pierre  Marie),  (see  St,  Observation  XXX,  reported  later).  In  other  cases 
there  is  in  addition  to  this  an  increased  growth  in  length,  leading  to  a  true 
giant  hand  (type  en  long  see  Ti,  Observation  XXV).  Here  are  found  both 
lengthening  and  broadening  of  the  hands  and  feet.  Launois  and  Roy  find  the 
type  en  long  in  acromegahc  gigantism.     The  feet  may  behave  similarly. 

X-ray  examination  of  the  skeleton  shows  a  thickening  of  the  walls  of  the 
skull,  enlargement  of  the  pneumatic  cavities,  increase  in  size  of  the  lower  jaw 
and  broadening  of  the  epiphyses  of  the  long  bones,  formation  of  osteophytes 
on  these,  thickening  of  the  phalanges  of  the  fingers  and  toes  {Schuller) ;  in  the 
later  stages  of  acromegaly  there  is  found  considerable  atrophy  of  the  osseous 
structure;  on  section  Deitnch  found  especially  the  spongiosa  atrophic.  He 
regards  this  as  neuropathic  atrophy.  Frankel,  Stadelmann,  and  Benda  in 
each  of  four  cases  found  pronounced  atrophy,  in  one  case  distinct  porosis  and 
always  formation  of  osteophytes. 

As  in  the  later  stages  the  muscles  of  the  arms  and  legs  are  for  the  most 
part  markedly  atrophic,  the  amorphic  condition  of  the  extremities  becomes 
that  much  the  more  conspicuous. 

As  example  of  the  skeletal  alterations  in  acromegaly  I  cite  the  following 
case: 

Observation  XXIV. — V.  U.,  thirty-two  years  old,  entered  the  clinic  Jan.  10,  1912,  car- 
penter. No  hereditary  predisposition  to  disease,  no  similar  sickness  in  the  family. 
Married  seven  years.  One  year  after  the  marriage  a  child  was  born  that  died  soon 
after  birth.     One  illegitimate  child  is  ten  years  old. 

The  present  disease  began  seven  years  ago  with  a  feeling  of  furriness  in  both  hands, 
formications,  and  a  characteristic  sensation  of  stiffness  especially  in  the  morning.  For 
some  months  severe  pains  in  the  hands  and  forearms  so  that  the  patient  had  to  get  up  often 
at  nights  and  walk  about  the  room.  Soon  afterward  the  patient  noticed  gradual  enlarge- 
ment of  the  hands,  and  a  short  time  after  this  the  chin  became  larger  so  that  chewing  was 


238 


THE    DISEASES    OF    THE    HYPOPHYSIS 


done  only  with  the  lateral  teeth,  as  also  the  jaw  was  pushed  forward.  The  pains  and  pares- 
thesias were  always  worse  in  summer  than  in  winter.  For  five  and  one-half  years  gradual 
loss  of  libido,  and  later  loss  of  erectihility  oj  the  penis.  Entirely  impotent  for  five  years. 
The  acromegalic  alterations  greatly  increased  in  intensity.  The  patient  denied  headache 
and  disturbances  of  vision.  Lately  there  have  reappeared  drawing  pains,  especially  in  the 
knees  and  ready  fatigal:)ility;  in  addition  to  these,  severe  sweats.  Alcoholism;  patient 
denies  lues. 

Status. — 168  cm.  tall,  coarsening  of  the  facial  features,  cushioning  of  the  lips,  circum- 
ference of  the  skull  58  cm.  Marked  protrusion  of  the  orbital  borders  and  the  frontal  pro- 
tuberances. Circumference  of  the  skull  from  the  point  of  the  chin  to  the  top  of  the  occiput 
74  cm.  Xose  coarse,  large,  lower  jaw  markedly  protruding,  lower  row  of  teeth  is  1.5 
cm.  anterior  to  the  upper  row.     The  lower  incisor  teeth  gape  3  mm.     Tongue  markedly 


Fig.  zZ-  ^^^^-  34- 

Case  of  acromegaly  (Observation  XXIV). 

thickened  and  broadened  and  on  account  of  the  thick  tongue,  articulation  is  poor.  Uvula 
broad,  tonsils  enlarged,  neck  broad  and  compressed  34}  2  cm.  in  circumference.  Submaxil- 
lary glands  palpable.     Thyroid  enlarged,  left  lobe  more  enlarged  than  right. 

The  skin  and  visible  mucous  membranes  somewhat  pale.  The  skin  rather  thick  but 
may  be  readily  raised  from  the  underlying  tissues  in  great  thick  folds.  The  hair  of  the 
head  rather  abundant,  the  hairiness  of  the  genitalia  rather  marked  and  also  the  thigh  and 
legs  are  rather  pronouncedly  covered  with  hair. 

Distinct  kyphosis  of  the  upper  dorsal  part  of  the  vertebral  column,  slight  lumbar 


ACROMEGALY  239 

lordosis.  Thorax  is  barrel  shaped,  compressed,  reaching  deep  downward  in  front.  Cir- 
cumference of  the  thorax  at  the  level  of  the  nipple  is  on  deep  inspiration  104  cm.,  on 
strong  expiration  loi  cm.  The  clavicles  are  markedly  thickened.  The  ribs  and  the 
intercostal  spaces  are  strikingly  broad.  The  upper  and  lower  extremilies  have  taken  on 
in  circumference  in  their  distal  parts.  Abnormal  breadth  of  the  middle  of  the  hand. 
Circumference  of  the  middle  finger  83.^  cm.  Right  hand  displaces  625  cc.  of  water, 
left  hand  640  cc.  of  water.  X-ray  examination  shows  chiefly  hypertrophy  of  the  soft 
pans.  The  metacarpi  are  biscuit-shaped  on  account  of  the  pressure  of  the  increased 
soft  parts  and  decrease  in  size  at  their  diaphysial  portions.  Also  the  middle  portion  of 
the  foot  is  enormously  broadened,  showing  a  similar  picture  to  the  X-ray.  Enormous 
thickening  of  the  toes. 

Transverse  diameter  of  the  heart  to  the  X-ray  13  cm.  Otherwise  cardiac  findings  normal. 
A  slight  decrease  of  tachycardia.  Liver  and  spleen  not  palpable.  On  X-ray  examina- 
tion the  stomach  is  not  enlarged. 

Examination  of  the  eye.  (Docent  Ullrich)  O.  D.  4^,  O.  S.  ^{o-  External  halves  of 
the  papillae  pale,  with  however  a  large  physiological  excavation  so  that  the  diagnosis 
paling  is  not  possible.     Visual  fields  for  white  and  colors  are  normal. 

X-ray  Examination  of  the  Skull. — Enormous  enlargement  of  the  entire  skull,  especially 
the  facial  bones.     Sella  turcica  enlarged  to  the  size  of  a  gulden.     Clivus  sharpened. 

Erythrocytes,  about  4,500,000. 

Hemoglobin,  75  per  cent. 

Leucocytes,  6,240  of  which: 

Polymorphonuclear  neutrophiles,  57.6  per  cent. 

Lymphocytes,  25.4  per  cent. 

Large  mononuclears,  15.7  per  cent. 

Eosinophiles,  1.3  per  cent. 

Examination  as  to  alimentary  glycosuria  was  unsuccessful,  as  the  patient  vomited 
No  sugar  in  the  urine  on  the  administration  of  a  diet  rich  in  carbohydrates. 

Pulse  between  go  and  100. 

Examination  of  the  exchange  of  gases  {Dr.  Bernstein) . 

CO2  O  Respiratory  CO2  O2 

quotient 
0.816  j 

0-793  }  3-156  3-857 

0.781  ] 

The  examination  of  the  elimination  of  uric  acid  on  a  purin-free  diet  shows  a  marked 
increase  of  the  endogenous  factor.  This  lies  higher  than  double  the  normal  average 
of  the  {Novaczinsky  and  Falta).'^ 

Examination  of  ammonia,  amino-acids,  and  polypeptid  elimination  shows  normal 
relations  as  may  be  seen  by  few  figures  here  adduced. 

N  N(NH3)  N.  (amino  acid)  N.  polyp. 

16.64  gm.  0.7202  0.2718  0.0683 

18.65  gm.  0.6902  0.2842  0.1561 

On  Feb.  28,  a  portion  of  the  hypophysis  of  the  patient  was  removed  by  the  endonasal 
route  by  Dr.  Hirsch. 

Mar.  5,  the  patient  was  retransferred  to  the  clinic. 

Mar.  15,  patient  has  fallen  off  in  weight  and  the  acromegalic  symptoms  have  not  as 

1  On  the  administration  of  sodium  nucleinate  there  was  a  prompt  and  rather  high  increase 
of  the  uric-acid  elimination. 


235-7 

288.8 

240.7 

296.3 

243.2 

298.4 

240 


THE    DISEASES    OF    THE    HYPOPHYSIS 


Fig.  35.— X-ray  picture  of  hand  in  acromegaly  (Observation  XX\"i. 


ACROilEGALY 


241 


yet  retrogressed.  Several  times  at  the  beginning  the  patient  showed  a  rise  in  temperature, 
but  at  present  the  temperature  is  normal.  Headaches  at  times.  Examination  of  the 
purin  metabolism  shows  just  as  decided  an  increase  of  the  endogenous  elimination  of  uric 
acid  as  before  the  operation. 

In  many  cases  the  muscle 
strength  is  not  diminished  in  the 
initial  stages.  Sometimes  such  in- 
dividuals show  even  an  extraordi- 
nary strength.  There  is,  however, 
from  the  beginning  a  gradually  in- 
creasing and  rapid  fatigability,  and 
in  the  later  stages  such  individuals 
cannot  long  follow  their  occupation 
on  account  of  muscular  weakness. 
Microscopically  such  muscles  show 
increase  of  the  connective  tissue 
and  degeneration  and  atrophy  of 
the  muscle  fibers.  Arnold  de- 
scribes vacuolization,  multiplica- 
tion of  the  nuclei,  and  atrophy  of 
the  muscle  fibers,  increase  in  the 
number  of  nuclei,  and  growth  of 
interstitial  connective  tissue,  also 
the  occurrence  of  fat  cells  in  the 
connective  tissues. 

Also  in  the  skin  are  found,  es- 
pecially in  the  sacral  parts,  sclerotic 
processes  affecting  both  the  epider- 
mis and  cutis.  The  papillae  are 
enlarged,  and  the  sclerosis  ex- 
tends to  the  nerves  and  vessels 
and  to  the  connective  tissue  fasci- 
culae  surrounding  the  glands.  Fre- 
quently abnormal  pigmentations 
are  found.  In  spite  of  sclerosing 
processes  the  skin  may  be  readily 
raised  up  in  folds,  which  fact  is 
important  in  the  differential  diag- 
nosis from  myxedema.  In  the 
later  stages  true  myxedematous 
alterations  of  the  skin  are  found  not  rarely  (see  below) . 

Pierre  Marie  found  mollusca  pendula  in  numerous  cases 


Fig.  36. — Abnormall}-  strong  growth   of  hair  in 
acromegaly  (Observation  XXV). 


The  secretion  of 


16 


242 


THE    DISEASES    OF    THE    HYPOPHYSIS 


Fig.  37. — -Widened  sella  turcica  in  acromegaly  (Observation  XXV). 


ACROilEGALY  243 

the  sebaceous  glands  is  increased   (see  below  for  information  concerning 
increased  sweat  secretion). 

The  growth  of  hair  on  the  head  is  often  remarkably  dense,  and  the  individual 
hairs  are  thick.  In  the  course  of  the  disease  abnormal  hair  growth  occurs 
on  the  trunk  and  extremities,  as  may  be  seen  in  the  follo\\ing  observation. 

Observatio7i  XXV. — T.,  thirty-one  years  old,  cobbler,  entered  the  clinic  Dec,  191 1. 
First  admitted  Nov.  16,  1905.  Since  1903  gradual  enlargement  of  the  hands.  All  mili- 
tary gloves  were  too  small  for  him.  Also  face  has  become  broader,  nose  and  lips  have 
become  larger,  weight  somewhat  less.  Headache,  pigmentations  of  the  skin,  thyroid 
slightly  enlarged.  Eye-grounds  normal.  No  hemianopsia.  Sella  turcica  uniformly 
enlarged  to  the  size  of  a  cherry.  The  dorsum  sell^  thinned.  The  clinoid  processes 
pushed  backward.  Skeleton  of  the  hands  and  feet  show  appreciable  thickening  of  the 
soft  parts. 

Nov.,  1907.  Headache  has  become  much  more  severe.  The  hairiness  of  the  body 
has  increased  markedy.  The  hairs  are  brittle.  Marked  hairiness  of  the  genitalia,  abnormal 
hairiness  of  the  abdomen  and  extremities. 

Arcus  supercihares  enormously  developed.  Nose  enlarged.  Lower  jaw  slightly 
prognathous.  Cushion-like  ear  lobules.  Mustache  bristly.  Hairiness  of  the  linea  alba 
very  strong.     Very  deep  wrinkle  formation  on  forehead.     Potency  entirely  normal. 

Sella  turcica  deepened  three  times  more  than  is  normal.  Dorsum  sellae  much  thinned 
and  elongated. 

Alimentary  glycosuria  negative. , 

Dec,  191 1.  During  the  last  year  the  hairiness  has  become  even  denser.  Libido  is  un- 
altered, the  potency  has  decreased  slightly.  Typical  acromegalic  alterations  of  the  skeleton 
and  the  soft  parts,  no  tachycardia.     Slight  enlargement  of  the  thjToid  gland. 

Investigations  of  the  Exchange  of  Gases  {Dr.  Bernstein) . 

Per  kg.   of  body  weight 
CO2  O2 

2-733  3-55 

Alimentary  glycosuria  strongly  positive  (0.78  gm.  dextrose) 
Erythrocytes,  4,490,000 
Hemoglobin,  95  per  cent. 
Leucocytes,  4900,  of  which: 
Polymorphonuclear  neutrophiles,  56.7  per  cent. 
Lymphocytes,  30.5  per  cent. 
Large  mononuclears,  12.6  per  cent. 
Eosinophiles,  0.2  per  cent. 
Investigation  of  the  elimination  of  uric  acid  on  purin-free  diet  shows  values  between 
0.72  and  0.97  gm. — therefore  is  very  appreciably  increased. 

The  foUomng  is  an  additional  example  of  abnormal  hairiness  in 
acromegaly. 

Observation  A'A'IT. — I.  Bo.,  thirty-one  years,  entered  ^Nlay,  191 1.  The  sickness  began 
in  1905.  First  enlargement  of  the  fingers,  then,  about  simultaneously,  enlargement  of  the 
feet,  the  skull,  the  nose,  the  neck.  In  1908  began  enlargement  of  the  lower  jaw.  Also 
the  ears  became  somewhat  thickened.  Since  1909  the  forearms  and  the  metatarsus,  too, 
have  grown.     Also  the  circumference  of  the  chest  has  increased  and  the  hairiness  of  the 


C02 

O2 

RQ 

233-5 

288.7 

0.809 

275-5 

342-0 

0-753 

266.7 

329.8 

0.748 

244 


THE    DISEASES    OF    THE    HYPOPHYSIS 


trunk  has  become  essentially  stronger.  Number  of  collar  formerly  41,  now  46.  For  two 
or  three  years  on  every  psychical  excitement,  and  less  on  every  bodily  movement,  in- 
stantaneous occurrence  of  outbreaks  of  sweats;  potency  not  entirely  normal  since  the  age  of 
twenty,  since  the  beginning  of  the  disease  rapid  diminution  of  libido,  and  now  it  is  lost 
utterly.  Appetite  increases  at  times.  In  1910  thyroidin  administered  at  home;  this  led  to 
palpitations  of  the  heart,  that  have  persisted  to  the  present.  Thyroidin  also  acted  unfavorably 
on  the  sweats.  A  cousin  of  his  father's  also  suffered  from  acromegaly.  For  six  or  seven 
months  headaches  on  the  vertex  and  occiput.  Power  of  attention  has  considerably 
decreased.  Often  cramps  of  the  musculature  of  the  feet,  and  calves,  and  sticking  pains 
in  the  bones  of  the  hands  and  feet. 


Fig.  38. — Case  of  acromegaly  (Observation  XX\"). 


Moderately  compact  body  build.  Head  enormously  big.  Orbital  margins  protrude. 
Root  of  nose  very  much  broadened.  Nose  very  thick,  lower  jaw  extraordinarily  massive. 
Lower  row  of  teeth  about  2  cm.  forward;  the  teeth  of  the  lower  jaw  stand  far  apart  from 
one  another.  The  color  of  the  face  is  pale.  Hair  of  the  head  dense  and  turns  gray  easily. 
Circumference  of  the  skull  62.5  cm.  Circumference  of  the  neck  45  cm.,  larynx  enlarged. 
Thyroid  gland  not  enlarged.  Enormous  growth  of  hair  on  thora.x.  Circumference  of  the 
thorax  107  cm.  on  inspiration,  q7  cm.  on  expiration.     Large  erectile  nipples. 

Pulse  56.     Extremities  enormously  thickened  in  the  distal  parts. 

For  example:  Circumference  of  each  thuml)  S.5  cm.,  circumference  of  middle  finger 
8.5  cm. 


ACROMEGALY 


245 


Erythrocytes,  5,210,000. 
Hemoglobin,  85  per  cent. 
Leucocytes,  8840,  of  which: 
Polymorphonuclear  neutrophils,  63.8  per  cent. 
Lymphocytes,  29.7  per  cent. 
Large  mononuclears,  4.2  per  cent. 
Eosinophiles,  2.3  per  cent. 

Alimentary  glycosuria  (100  gm.  dextrose)  negative. 
Pituitrinum  infundibulare  (2  cc.)  no  influence  on  diuresis,  no  glycosuria. 


Fig.  39. — Abnormally  strong  growth  of  hair  in  acromegaly. 

X-ray  examination  {Docent  Schiiller)  skull  thick  with  enormous  frontal  sinuses.  Sella 
markedly  widened,  dorsum  sellae  lengthened,  coarse,  reclining;  anterior  clinoid  process 
broad,  no  sphenoidal  sinuses. 

Eye  examination  {Prof.  Sachs) .     Vision  and  field  of  vision  normal. 

Operation  was  undertaken  by  Dr.  Hirsch  on  May  29,  under  local  anesthesia,  by  the 
endonasal  route.  For  the  details  I  refer  to  0.  Hirsch's  publications.  The  cavity  made 
in  the  hypophysis  by  operation  reached  about  23^  cm.  in  the  sagittal  and  i]yi  cm.  in 
the  vertical  diameter.  The  temperature  rose  to  38.0°  transitorily,  falling  back  to  normal 
in  a  few  days.  On  June  2,  the  patient  already  made  the  observation  that  the  size  of  the 
end-phalanges  of  the  fingers  had  decreased.  There  must  also  have  occurred  a  diminution 
in  the  size  of  the  feet,  for  the  slippers,  which  were  formerly  too  small,  now  fit  him.     On 


246  THE    DISEASES    OF    THE    HYPOPHYSIS 

June  3,  the  patient  observed  that  his  hat,  that  also  had  been  too  small,  now  fell  down 
on  his  forehead.  On  June  9,  an  improvement  in  the  attention  became  apparent.  The 
patient,  who  was  a  doctor  of  mathematics,  could,  before  the  onset  of  his  illness,  repeat 
all  of  12  two-digit  figures  that  were  told  to  him  at  intervals  of  five  seconds.  Before  the 
operation  he  could  remember  only  7.  Now  he  regularly  repeated  11.  June  11,  the 
greatest  circumference  of  the  head  which  before  the  operation  reached  62.5  cm.,  is  now 
61.4  cm.  The  greatest  circumference  of  the  neck,  formerly  46  cm.,  now  is  43  cm.  The 
water  displacement  of  the  hands  which  formerly  was  700  cc.  is  now  600  cc.  The  thicken- 
ings about  the  eyes  have  now  retrogressed,  and  the  soft  parts  of  the  cheeks  and  chin  have 
also  distinctly  fallen  off.     On  June  19,  the  patient  left  for  his  home. 

Histological  examination  of  the  material  obtained  on  operation  {D.  Erdheim)  showed 
an  adenoma  consisting  in  small  round  cells  that  look  alike,  with  round  vesicular  nuclei 
and  a  well-developed  protoplasm;  at  regular  intervals  the  tissue  is  permeated  with  blood- 
vessels with  capillary  walls,  giving  to  the  tumor  a  trabecular,  in  some  places  an  alveolar, 
appearance.  At  places  proliferation  and  hyaline  degeneration  of  the  stroma,  often  with 
extensive  hemorrhage.  I  mention  briefly,  from  the  patient's  report  in  July  that  the  sweats 
have  improved  considerably,  from  his  report  in  August  that  the  circumference  of  the  head 
has  decreased  still  more,  the  thirst  has  subsided,  but  there  has  been  no  alteration  in  the 
vita  sexualis.  In  January,  1912,  he  reported  that  retrogression  of  the  acromegalic  mani- 
festations had  not  gone  further;  that  lately  even  an  aggravation  had  set  in,  this  consisting 
in  the  fact  that  the  tongue  had  become  thicker,  the  mental  attitude  was  that  of  depression, 
the  thirst  had  again  become  greater,  but  there  was  no  more  polyphagia. 

Often  too  the  eyebrows  became  bushy.  In  women  often  hairs  develop 
on  the  upper  lip,  and  bristly  hairs  on  the  chin  and  on  the  lower  lip,  similar  to 
the  chin-beard  in  man.  also  hairs  on  the  cheeks,  and  especially  on  the  inner 
side  of  the  thigh  and  even  on  the  linea  alba  (also  a  case  of  Stiimme  s) .  This 
occurrence  of  abnormal  hairiness  in  women  is  illustrated  by  the  following 
case: 

Observation  XXVII. — E.  T.,  thirty-three  years,  entered  Nov.,  1909.  Menstruated 
first  at  the  age  of  twelve  years,  followed  regularly  at  intervals  of  four  weeks,  the  flow 
lasting  eight  days,  profuse.  Lues  at  the  age  of  nineteen  years,  primary  sore  on  the  left 
labium  minor,  twelve  injections,  after  six  weeks  papules  in  the  genitals,  nineteen  inunc- 
tions. The  end  of  1895,  an  abortion,  and  1898  apparently  a  purulent  parametritic  exu- 
date, 1907  another  abortion. 

The  present  illness  began  in  1902  and  within  one-half  year  had  attained  almost  its 
present  intensity.  First  paresthesias  in  the  upper  extremities  and  shoulders,  then  thick- 
ening of  the  fingers,  so  that  the  patient  had  to  discard  her  rings.  A  half  year  later  en- 
largement of  the  feet,  so  that  the  shoes  became  very  much  too  small.  At  the  same  time 
occurred  enlargement  of  the  lips  and  nose.  The  circumference  of  the  neck  had  increased 
about  4  cm.,  the  abdomen  also  became  thicker,  and  hair  began  to  grow  on  the  breast  and 
calves.  The  breasts  did  not  become  especially  larger,  but  milk  began  to  be  secreted  by  them. 
Periods  extremely  irregular,  at  one  time  remained  away  for  seventeen  months,  libido 
at  first  increased,  then  diminished.  The  voice  right  at  the  onset  became  deeper.  Lately 
frequent  outbreaks  of  sweat.  Occasional  voracious  hunger  and  great  thirst.  Often 
frontal  headache. 

Typical  acromegalic  appearance.  Hands  and  feet  enormously  large.  Skin  very 
moist,  marked  hairiness  of  both  arms,  hairs  between  the  breasts  and  on  the  genitals,  the  hairs 
of  the  mans  veneris  reach  as  high  as  the  navel.     Hairiness  therefore  that  of  a  man.     Cir- 


ACROMEGALY  247 

cumanal  and  perineal  hairs  abundant.  Also  the  leg  is  markedly  covered  with  hair.  Nose 
and  lips  markedly  thickened,  lower  jaw  protrudes  rather  strongly.  The  incisor  teeth  of 
the  lower  jaw  are  far  apart  from  each  other.  Tongue  very  much  more  enlarged.  Thy- 
roid enlarged.  Colostrum  can  be  expressed  from  the  breasts  on  light  pressure.  Eye-grounds 
and  field  of  vision  normal.  Lordosis  of  the  lumbar  spine.  Enlargement  of  the  nose  and 
lower  jaw,  hands,  and  feet.  X-ray:  Sella  turcica  much  widened,  as  big  as  a  crown  piece. 
The  posterior  ciinoid  process  consumed. 

Dec.  3 — 100  gm.  dextrose — 3.58  gm.  dextrose  in  urine.     On  a  purin-free  diet  the  values 
of  uric  acid  were  0.765,  0.720,  1.204,  1-296,  1.050,  1.097,  i-oSo,  0.762,  1.155,  i.oii,  0.855. 

Blood  examination  erythrocytes,  4,975,000. 

Hemoglobin,  12  gm. 

Leucocytes  5600,  of  which: 

Polymorphonuclear  neutrophiles,  76  per  cent. 

Lymphocytes,  22  per  cent. 

Eosinophils,  2  per  cent. 


Fig.  40. — Case  of  acromegaly. 

Dec.  8 — o.ooi  gm.  adrenalin  subcutaneously.  Pulse  gradually  rose  from  72  to  102. 
Blood-pressure  from  95  to  115.  After  twenty  minutes  return  to  normal.  Slight  head- 
ache, tremors,  slight  arrhythmia,  considerable  increase  in  diuresis,  no  sugar. 

Abundant  carbohydrate  diet  leads  to  glycosuria. 

Dec.  14 — o.ooi  gm.  adrenalin  subcutaneously.  Pulse  from  72  to  96,  blood-pressure 
from  115  to  125,  slight  headache,  slight  arrhythmia,  no  sugar,  diuresis  from  950  to  2000. 

Dec.  15 — I  cc.  pituitrinum  infundibulare,  marked  diuresis,  no  sugar. 

Dec.  16 — 100  gm.  dextrose,  sugar  strongly  positive. 

Dec.  17 — 100  gm.  dextrose,  in  urine  2.1  gm.  dextrose. 

Dec.  21 — o.oi  gm.  pilocarpine,  moderate  sweating,  moderate  flow  of  saliva. 


248  THE    DISEASES    OF    THE    HYPOPHYSIS 

Very  noteworthy  in  acromegaly  are  alterations  in  the  genitalia,  that  is, 
the  manifestations  that  may  be  ascribed  to  functional  alterations  of  the  sexual 
glands.  We  shall  see  later  that  for  the  comprehension  of  especially  the 
genital  disturbances  in  acromegaly  and  for  the  pathogenesis  and  theory  of 
acromegaly  in  general  there  seems  necessary  a  sharp  distinction  between  the 
function  of  the  interstitial  glands  and  the  generative  glands,  at  least  so  far  as 
this  is  possible,  according  to  our  present-day  knowledge.  As  will  be  seen 
from  the  description  of  the  alteration  in  the  hairiness,  there  is  almost  never 
found  in  acromegaly  a  retrenchment  of  the  so-called  secondary  sexual 
characters  and  a  retrogression  of  the  external  genitalia.  An  exception  to 
this  is  perhaps  certain  cases  of  acromegaly  in  childhood,  which  I  shall  speak 
of  in  detail  later.  In  acromegaly  of  adults,  on  the  contrary,  there  is  mostly 
sharp  accentuation  of  the  secondary  sexual  characters.  As  has  been  men- 
tioned there  is  often  seen  a  strikingly  strong  development  of  the  hairs  of  the 
beard;  the  axillary  hairs,  the  hairs  on  the  genitalia  and  on  the  perineum  grow 
more  strongly,  and  often  there  develops  a  marked  hairiness  along  the  linea 
alba;  the  hairiness  in  women,  as  v.  Xoorden  mentions,  often  assumes  in  this 
case  a  virile  type.  Moreover  the  external  genitalia  often  show  a  distinct 
hyperplasia.  The  penis,  the  labia  majora  and  the  clitoris  may  appreciably 
increase  in  dimensions. 

These  phenomena  persist  until  the  end  of  the  disease.  In  certain  cases 
we  can  at  least  say  that  a  distinct  retrogression  does  not  occur. 

The  function  of  the  glands  of  generation  behaves  otherwise.  Here  we 
mostly  find  premature  lessening  or  loss  of  function.  There  are,  however, 
numerous  exceptions,  that  I  shall  speak  of  first.  At  the  beginning  of  the  dis- 
ease there  is  found  not  at  all  rarely  signs  of  the  increased  function.  Thus 
there  was  for  instance  at  the  beginning,  in  the  case  of  Biiday  and  Janczo 
(acromegalic  gigantism)  increased  potency. 

In  women,  too,  libido  may  be  increased  at  the  beginning;  I  here  allude  to 
Observation  XXVII.  In  this  case  the  illness  had  lasted  seven  years;  in  spite 
of  this  menstruation,  although  irregular,  persisted;  the  libido  at  first  in- 
creased, later  decreased.  Colostrum  could  be  expressed  from  the  breasts. 
Cases  of  persistent  galactorrhea  have  been  described  by  Gajklevicz  and  Fazio. 
In  other  cases  the  function  of  the  glands  of  generation  last  until  in  the  fully 
developed  disease.  I  refer  to  Observation  XXV.  In  this  case  the  disease 
began  in  1903,  in  the  year  1907  the  potency  and  libido  were  entirely  normal, 
1911  the  libido  was  as  yet  entirely  retained,  but  the  potency  had  to  a  certain 
extent  diminished. 

In  such  cases  signs  of  increased  activity  of  the  sexual  glands  may  be  found 
at  autopsy.  Thus  Schidtze  and  Fischer  state  that  in  a  man  aged  lifty-six 
(Case  2)  in  whom  the  acromegaly  had  lasted  seven  years,  strikingly  abun- 
dant spermatogenesis  was  to  be  found  in  the  testicles,  and  the  prostate  was 
enlarged  and  in  a  condition  of  abundant  secretion. 


ACROMEGALY 


249 


The  following  case,  although  not  so  instructive,  seems  a  further  example  of 
the  preservation  of  the  generative  function: 

Observation  XXVIII. — F.  Da.,  thirty-eight  years  old.  Ambulant  patient  in  igii. 
For  nine  years  married,  three  children.  Wife  has  had  one  abortion;  for  about  one  and 
one-half  years  the  hands  and  feet  have  become  thickened,  etc.  Collar  number  has  risen 
from  41  to  44,  hat  number  from  55  to  583^.  One  year  ago  the  incisor  teeth  spread 
apart  from  each  other,  and  the  lower  jaw  projected.  Often  polydipsia.  Dyspnea  on 
ascending  stairs.  More  readily  excited  than  formerly.  Body  weight  has  increased  from 
7  kg.  to  83  kg.  Arching  of  the  chest  has  increased.  Potency  not  altered.  Typical 
acromegaly.     External  genitalia  strongly  developed,  large  amount  of  hair  on  them. 


gm. 


Fig.  41. — Case  of  acromegaly  (Observation  XXIX). 

Erythrocytes,  5,300,000. 

Hemoglobin,  90  per  cent. 

Leucocytes,  8100,  of  which: 

Neutrophiles,  74  per  cent. 

Lymphocytes,  20  per  cent. 

Eosinophiles,  6  per  cent. 
Test  as  to  alimentary  glycosuria  (100  gm.  dextrose) — in  urine  1.3  per  cent.  =  0.88 
[. 
Eye  findings  normal,  sella  turcica  almost  the  size  of  a  gulden  piece. 


Menstruation  may  be  present  for  a  long  time  in  acromegalic  women. 
In  Becker's  case  the  menstruation  ceased  as  late  as  eighteen  years  after  the 


250 


THE    DISEASES    OF    THE    HYPOPHYSIS 


beginning  of  the  affection;  in  a  case  of  Dobbelm's  there  was  entirely  normal 
genital  function.  A  short  time  ago  I  even  saw  a  case  in  which  it  was  very 
likely  that  in  a  course  of  a  very  chronic  acromegaly  conception  had  occurred 
several  times,  and  children  had  been  carried  to  term.  I  here  quote  the  case 
in  extenso: 


Observation  XXIX.~S.  Ad.,  fifty-six  years  old.     Entered  the  clinic  Oct.,  1912.     The 
ather  of  the  patient  seems  to  have  been  rather  vigorous,  and  in  his  later  years  his  condi- 
tion seems  to  have  exhibited  some  resemblance  to  the  patient.     From  the  age  of  fifty- 


ACROMEGALY  251 

six  years  on  his  face  became  broader.  He  died  of  pneumonia  in  his  seventieth  year. 
No  ductless  glandular  diseases  in  the  family.  The  patient  has  seven  brothers  and 
sisters,  all  well.  She  has  five  children,  the  first  child  born  when  she  was  in  her  twenty- 
eighth  year,  the  last  when  she  was  in  her  fortieth  year.  All  the  births  were  normal, 
and  all  the  children  were  well  developed.  Menstruated  first  at  the  age  of  twenty-two 
years,  the  menses  were  always  rather  profuse,  lasting  two  to  three  days,  and  occurring 
regularly  every  four  weeks,  menopause  at  the  forty-sixth  year.  For  two  years  headaches, 
especially  at  the  roof  of  the  skull  of  the  right  side,  which  headaches  have  increased  in 
intensity.  The  pains  now  exist  day  and  night  and  for  the  most  part  are  so  intense 
that  the  patient  cannot  sleep.  During  the  last  four  to  five  months  she  has  always 
remained  in  bed  on  account  of  these  headaches,  and  on  account  of  the  fact  that  when 
she  attempted  to  get  up  she  would  suffer  with  attacks  of  vertigo.  The  patient  had 
also  had  headaches  for  some  time  before  this  but  she  did  not  give  them  much  attention. 
She  states  definitely  that  the  enlargement  of  the  hands  and  feet  developed  gradually 
between  the  twentieth  and  thirtieth  year  of  life.  At  the  time  of  the  birth  of  her  first 
child  in  her  twenty-eighth  year  the  hands  and  feet  were  much  larger  and  thicker  than 
at  present,  and  have  gradually  decreased  in  circumference.  Also  the  prognathism 
of  the  lower  jaw  has  existed  since  that  time.  She  never  suffered  from  sweats  or  from 
pains  in  the  extremities. 

The  patient  looks  at  least  fifteen  to  twenty  years  older  than  she  is.  Height  145.5 
cm.,  span  width  150.5  cm.  Layer  of  fat  well  developed.  Skin  pale,  smooth  and  dry, 
musculature  weak,  build  of  bones  medium,  considerable  kj-phosis;  the  extremities  are 
extraordinarily  heavy,  head  large,  fronto-occipital  circumference  56  cm.,  nose  large  with 
broad  insertion;  distance  from  between  the  eyebrows  to  the  tip  of  the  nose  5.8  cm.; 
breadth  of  the  nose  4.5  cm.,  distinct  prognathism.  From  temporomaxillary  joint  to 
temporomaxillary  joint,  over  chin,  26  cm.  Lower  lips  thick,  cushiony,  and  prominent. 
The  teeth  are  in  greater  part  absent,  the  two  lower  incisor  teeth  are  present  and  are 
spread  apart  from  each  other.  The  clavicles  are  rather  broad;  the  extremities  extraor- 
dinarily awkward.  The  fingers  are  markedly  thickened  and  the  X-ray  shows  that  the 
thickening  affects  the  weak  spots  exclusively.  The  metacarpal  bones  are  pushed  apart 
from  each  other,  only  very  slight  bone  formation  at  the  seat  of  the  muscular  insertions. 
Also  the  feet  are  awkw^ard.  AxUlary  hair  and  pubic  hair  well  developed.  Isolated 
hairs  on  the  upper  lips.     Slight  arteriosclerosis. 

Alimentary  glycosuria  (100  gm.  dextrose),  0.8  gm. 
Blood  findings:  Leucocytes,  9800,  of  which: 
Polymorphonuclear  neutrophiles,  66  per  cent. 
Lymphocytes,  30  per  cent. 
Large  mononuclears,  3  per  cent. 
Eosinophiles,  i  per  cent. 

One  week  later  repetition  of  the  test  for  alimentary  glycosuria  after  two  injections 
4  cm.  pituitrinum  glandulare  intramuscularly  (100  gm.  dextrose)  0.9  gm. 

X-ray  examination  of  the  skull  {Dr.  Schwarz) :  Widening  of  the  sella  turcica  to  the  size 
of  a  2-crown  piece.  Deepening  of  the  floor  of  the  selte,  processus  clinoidei  sharpened. 
Entrance  to  the  sellse  widened. 

Eye  examination  (Docent  Ulhrich)  papillee  normal,  the  inner  borders  slightly  effaced 
and  slightly  prominent.  Nothing  certainly  pathological;  on  the  contrary,  vision  O.  D. 
3/36,  0.  S.  1/36,  but  there  is  an  old  trachoma  with  corneal  scars;  visual  field  on  each  side, 
so  far  as  can  be  tested,  normal;  also  normal  for  colors. 

The  examination  of  the  uric-acid  elimination  on  purin-free  diet  shows  values  between 
0.4-0.5  gm.,  therefore  no  increase. 


252  THE    DISEASES    OF    THE    HYPOPHYSIS 

As  far  as  I  have  been  able  to  find,  a  similar  case  of  conception  in  acro- 
megaly has  been  reported  only  by  Pirie. 

However,  in  the  great  majority  of  cases  of  acromegaly,  as  has  already 
been  mentioned,  there  occur  sooner  or  later  signs  of  extinction  of  the  function 
of  the  generative  glands.  This  may  occur  even  early,  constituting  a  differ- 
ential diagnostic  difficulty.  In  man  there  soon  comes  to  pass  lessening  or 
complete  loss  of  potency  and  libido,  and  in  woman  amenorrhea.  As  the  latter 
is  attended  with  a  cessation  of  ovulation,  it  may  very  well  be  supposed  that  as 
yet  no  case  of  conception  has  been  observed  in  an  amenorrheic  acromegalic 
woman. 

In  such  cases  the  sexual  glands  and  the  internal  generative  organs  gradu- 
ally atrophy.  Tandler  and  Grosz  found  total  retrogression  of  the  primordial 
follicles  and  cessation  of  the  formation  of  Graafian  follicles,  and  in  man 
alteration  of  the  epithehum  of  the  seminal  tubules  and,  finally,  also  alteration 
of  the  interstitial  cells.  On  gynecological  examination  the  uterus  is  usually 
found  to  be  small.  Not  rarely  cystic  degeneration  of  the  ovaries  is  also 
present.  Atrophy  of  the  internal  genitalia  was  found  in  36.4  per  cent,  of 
118  cases,  according  to  the  statistics  of  Creutzfeldt. 

That  even  on  long-continued  amenorrhea  the  follicular  apparatus  may  not 
degenerate  entirely  is  shown  by  a  case  of  Cagnetto;  menstruation  ceased  at  the 
age  of  nineteen  years;  at  the  age  of  forty-six  years  it  reappeared  and  continued 
to  the  age  of  forty-eight  years,  when  it  disappeared  for  good;  autopsy  showed 
cystic  degeneration  of  the  tumor  of  the  pituitary;  in  this  case  it  is  not  unhkely 
that  the  h}^erfunction  was  restricted  by  the  cystic  degeneration. 

We  may  therefore  briefly  sketch  the  relation  between  hj'pophysis  and 
sexual  glands,  thus:  increased  activity  of  the  hypophysis  stimulates  the  ac- 
tivity of  the  interstitial  glands  (apparently  also  the  suprarenal  cortex). 
The  glands  of  generation  are  sometimes  also  stimulated  to  increased  activity 
at  first,  but  more  often  the  activity  is  suspended.  Conversely  we  find  that 
on  increased  activity  of  the  sexual  glands  there  is  also  increased  activity 
of  the  hypophysis.  I  beheve,  in  opposition  to  the  prevaihng  teaching,  that 
there  is  in  pregnancy  an  increased  activity  of  the  sexual  glands,  as  I  regard 
the  developing  fetus  as  a  prolonged  ovulation  (see  chapter  on  the  sexual 
glands) — there  is  found  enlargement  of  the  hypophysis  and  signs  of  an  in- 
creased function  of  that  organ,  coarsening  of  the  facial  features,  etc.  {Tandler 
and  Grosz).  Indeed  a  transitory  acromegaly  may  even  occur  during  this 
period.  Such  a  case  is  reported  by  R.  Marek.  Pronounced  acromegalic 
symptoms  occurred  during  pregnancy  in  a  twenty-seven-year-old  primipara. 
Nose,  tongue,  and  jaws  became  larger,  the  teeth  spread  apart,  the  hands  and 
tongue  increased  in  circumference,  the  tonsils  swelled,  glycosuria,  lassitude, 
sleeplessness  and  insomnia,  and  also  drawing  pains  in  the  muscles  made 
their  appearance.     All  signs  disappeared  during  the  puerperium. 

In  such  cases  of  formes  frustes  of  acromegaly  during  pregnancy,  we  may 


ACROMEGALY  253 

think  very  plausibly  of  an  existing  predisposition;  we  might  also  be  inclined 
to  beheve  that  repetition  of  the  pregnancy  would  lead  to  permanent  manifes- 
tation of  the  disease. 

Goiters  and  alterations  in  the  function  of  the  thyroid  occur  in  acromegaly  with 
great  frequence.  The  development  of  the  goiter  may  occur  about  simulta- 
neously with  that  of  acromegaly,  and  thus  symptoms  of  hyperthyrosis  or  hypo- 
thyrosis  may  become  manifest  simultaneously  with  acromegalic  symptoms. 
Manifestations  of  a  slight  hyperthyrosis  in  acromegaly  are  especially  common. 
Magnus-Levy  and  Salamon  have  especially  directed  attention  to  this  subject. 
Later,  in  the  consideration  of  the  manifestations  on  the  part  of  the  vegetative 
nervous  system,  we  shall  see  that  among  the  more  frequent  symptoms  in 
acromegaly  are  sweats.  We  shall  have  to  consider,  however,  whether  we  are 
justified  in  regarding  them  as  a  symptom  of  a  simultaneous  hyperfunction,  and 
whether  they  do  not  signify  rather  that  certain  organs  of  supply  of  the  vegeta- 
tive nervous  system  are  not  directly  influenced  by  the  irritation  of  these 
nerves,  on  account  of  the  hyperfunction  of  the  hjrpophysis.  A  tachycardia 
might  be  regarded  as  a  surer  symptom  of  hyperthyrosis  especially  when  there 
exists  thyroid  swelling  and  increased  fall  in  blood-pressure. 

In  case  U  (Observation  XXIV)  the  thyroid  was  enlarged.  There  existed 
profuse  sweats  and  a  slight  grade  of  tachycardia.  Slight  enlargement  of  the 
thyroid  was  present  also  in  case  T,  Observation  XXV,  but  in  this  case  symp- 
toms of  hyperthyrosis  were  not  distinct. 

Of  the  remaining  symptoms  of  Basedow's  the  following  have  been  stated 
to  have  occurred  in  the  course  of  acromegaly:  tremor,  transitory  rises  of 
temperature,  cardiac  palpitation,  increased  psychical  irritability. 

The  following  is  a  very  instructive  example  of  the  simultaneous  develop- 
ment of  acromegaly  and  a  slight  hyperthyrosis. 

Observation  XXX. — M.  St.,  thirty-seven  years  old.  First  admission  at  hospital  in  De- 
cember, 1896.  Menses  appeared  first  at  the  eighteenth  year,  and  were  regular  up  to  the 
twenty-fourth  year  of  life.  From  then  on  they  remained  absent.  At  the  thirty-first  year 
tearing  pains  in  all  the  members  appeared,  especially  at  night.  The  fingers  were  swollen, 
and  there  were  sometimes  intense  sensations  of  heat.  Since  that  time  there  have  existed 
severe  headaches.  Finally  there  developed  about  this  time  a  goiter.  In  addition  there 
appeared  pains  in  the  neighborhood  of  the  thyroid  gland,  which  recurred  every  month.  Lately 
forgetfulness,  lassitude,  and  weakness.     The  motor  power  has  weakened. 

Typical  acromegaly  and  thickening  of  the  nose,  hands  and  feet.  Circumference  of  the 
throat  44  cm.  Slight  degree  of  anemia.  (Hemoglobin  65  per  cent.,  erythrocytes  4,000,- 
000.)  Enormous  struma  of  the  thyroid,  both  lobes  diffusely  enlarged,  with  circumscribed 
nodules,  no  hemianopsia,  no  disturbances  of  vision.     Shght  kyphosis. 

Second  admission,  March,  1892.  Now  marked  kyphoscoliosis.  The  acromegaly  has 
advanced. 

Third  admission,  August,  1899. 

Fourth  admission,  December,  1899.  Fine  tremor,  exophthalmus,  tachycardia,  marked 
alimentary  glycosuria  2.25  per  cent,  dextrose  in  urine  when  100  gm.  dextrose  administered. 

To  100  gm.  levulose.  Trammer  at  times  distinctly  positive. 


2  54  THE    DISEASES    OF    THE    HYPOPHYSIS 

Fifth  admission,  May,  1907.  For  two  years  there  has  been  a  gradual  diminution  in  the 
motor  power.  Goiter  seems  to  be  smaller.  Appreciable  enlargement  of  the  sella  turcica. 
The  enlargement  of  the  hands  depends  only  on  the  enlargement  of  the  soft  f)arts.     Frontal 


Fig.  43. — X-ray  picture  of  the  hand  in  acromegaly  (ig  natural  size). 

cavities  enormously  widened.     Eye-findings  normal.     Alimentary  glycosuria   (50  gm.) 
now  negative.     Death  from  pneumonia. 

Autopsy. — Tumor  of  the  hypophysis  of  soft   confluent  consistence  and  grayish-red 
color.     Besides,  in  various  organs,  numerous  tuberculomata. 


ACROMEGALY 


255 


In  this  case  then  in  the  thirty-first  year  of  life  the  goiter  appeared  simulta- 
neously with  acromegaly,  the  goiter  subsequently  developed  enormously  and 


led  to  pronounced  symptoms  of  hyperthyrosis  (tremor,  exophthalmus,  tachy- 
cardia, etc.).  Also  the  alimentary  glycosuria  could  have  been  a  symptom  of 
the  hyperthyroidism,  at  least  it  disappeared  later,  when  the  goiter  became  re- 


256  THE    DISEASES    OF    THE    HYPOPHYSIS 

duced.  Such  a  retrogression  of  a  preceding  goiter  occurs  frequently  in  the 
later  stages  of  acromegaly.  With  its  disappearance  may  be  associated  not 
only  a  disappearance  of  the  Basedow's  symptoms,  but  also,  as  in  this  case,  the 
appearance  of  symptoms  of  true  myxedema. 

Ohservaiion  XXXI. — A.  .Sir.  First  entered  the  clinic  in  February,  1896,  then  thirty- 
one  years  old. 

Chlorosis  at  the  age  of  eighteen  years.  Menstruated  first  at  the  age  of  fifteen  years; 
menstruation  was  regular  until  her  marriage  in  her  twenty-first  year.  Pregnancy  and 
delivery  normal,  child  well.  Since  that  time  has  never  menstruated,  and  has  become  pro- 
gressivel}^  weaker.  Two  years  after  the  confinement  (1898)  the  hands  and  feet  began  to 
become  thicker  and  coarser,  the  wedding  ring  had  to  be  filed  off  and  enlarged,  and  it  had 
to  be  made  even  larger  in  1890  and  1893  respectively.  Also  the  shoes  had  to  be  made 
larger.  The  rest  of  her  body  became  always  thicker  and  more  awkward,  the  neck 
became  swollen,  but  the  breasts  became  progressively  smaller.  The  facial  features  altered 
more  and  more  so  that  at  times  she  was  not  recognized  as  herself  by  good  friends.     In  spite 


Fig.  45a. — Before  the  disease.  Fig.  45^. — At  the  height  of  the  disease. 

Case  of  acromegaly. 

of  the  increase  in  body  she  became  progressively  weaker.  Burning  pains  in  the  fingers  oc- 
curred early  in  the  course  of  the  disease,  pains  that  were  increased  at  night  by  the  warmth 
of  her  bed.  Later  were  added  day-sweats  and  night-sweats,  so  that  night-clothing  and  bed- 
linen  had  to  be  changed  several  times  during  the  night.  The  eyes  protruded  distinctly. 
Occasionally  she  had  headache  and  vertigo.  Speech  became  rough  and  nasal,  the  tongue 
has^become  heavier,  thicker  and  longer,  so  that  it  was  often  caught  by  the  teeth  when 
she  spoke.  Formerly  set  of  teeth  was  quite  regular.  At  present  the  anterior  incisor 
teeth  of  the  lower  jaw  incline  outward,  are  spread  apart  from  each  other,  and  do  not  fit 
those  of  the  upper  jaw.  At  first  she  suft"ered  with  constipation;  often  there  was  no 
evacuation  for  fourteen  days,  latterly  she  often  has  diarrheas.  She  is  very  nervous,  and 
frequently  has  cardiac  palpitations  and  difiiculty  in  breathing.  Slight  tremor.  The 
powers  of  memory  have  suffered,  the  [mental]  altitude  is  depressed  and  she  is  easily  excited. 

Circumference  of  skull,  57.7  cm. 

Length  of  nose,  5.5.  cm. 


ACROMEGALY 


257 


Distance  apart  of  the  alae  of  the  nose,  4.2  cm. 

Circumference  of  the  neck,  40.0  cm. 

Circumference  of  the  waist,  86  cm. 

Height,  163  cm. 

Eye-grounds  and  perimetry  normal. 

Second  entrance,  January,  1901.  There  now  exist  slight  swellings  of  certain  joints, 
especially  of  the  knee  and  elbows,  where  crepitation  is  present  on  palpation.  The  cardiac 
oppression  has  become  intense.  The  voice  seems  to  have  improved.  The  distance 
between  the  middle  and  upper  incisors  is  now  about  i  mm.,  that  between  the  lower  middle 
incisors  9  mm.  The  tongue  is  enormous;  hands  and  feet  have  greatly  broadened.  The 
tubera  parietalia  project  markedly,  and  does  also  the  arcus  superciliares;  alae  of  the  nose, 
the  lips  and  lower  jaw  have  enlarged  enormously.  The  spinous  processes  are  sensitive 
to  pressure.  Pain  in  the  entire  vertebral  column  is  elicited  by  pressure  on  the  head. 
Eye  findings  normal.     The  circumference  of  the  throat  has  increased- about  3  cm. 

Third  entrance  to  clinic,  January,  1903.  Attacks  of  frontal  headache  with  insomnia. 
Alimentary  glycosuria,  a  trace  of  sugar  on  the  ingestion  of  100  gm.  dextrose. 


Fig.  46. — Acromegalic  and  normal  hands. 


Fig.  47. — Acromegalic  feet. 


Gynecological  examination:  Flat  pelvis  with  very  slight  osteomalacic  changes.  Pain- 
fulness  of  the  bones,  Chvostek's  phenomenon  positive  ^  One  time  it  was  possible  to  elicit 
Trousseau's  sign. 

Flexion  of  the  hip-  and  knee-joints  much  restricted.  Spasms  of  the  adductors.  The 
knee-joints  greatly  distended,  crepitation.  Electrical  irritability  normal.  Eye  findings 
normal. 

Erythrocytes,  4,278,000. 

Hemoglobin,  10.2  gm. 

Leucocytes,  2900,  of  which: 

Polymorphonuclear  neutrophiles,  6  per  cent. 

X-ray:  Skull  capsule  thickened.  Sella  turcica  irregularly  widened,  clinoid  processes 
hyperostotic.  The  thickening  of  the  extremities  affects  the  soft  part  exclusively.  The 
bones  are  atrophic. 


^  On  account  of  these  manifold  symptoms,  the  case  was  exhibited  by  A .  Miiller  before  the 
Wiener  Gesellschaft  f .  innere  Medizin  und  Kinderheilkunde. 
17 


258  THE    DISEASES    OF    THE    HYPOPHYSIS 

Fourth  entrance  to  the  dinic.  April,  1909.  Copious  night-sweats,  cardiac  palpita- 
tions.    Circumference  of  the  throat  38  cm.     Ah'mentar>-  glycosuria  negative. 

Pigmentation  on  the  face,  hands,  and  neck  o.ooi  gm.  adrenalin  subcutaneously,  no  sugar. 

Fifth  entrance  to  the  clinic,  November,  1909.  Circumference  of  the  neck  35  cm. 
Heart  enlarged,  extra  systoles;  Chvostek  negative. 

Sixth  entrance  to  the  cUnic,  April,  1910.  Alimentary  gljxosuria  (100  gm.)  negative. 
Adrenalin  o.ooi  gm.,  no  sugar. 

Three  thyroidin  tablets  administered  thrice  daily  for  three  daj-s,  the  pulse  rate  was 
somewhat  increased.  Cardiac  palpitations  slight,  the  neutrophilic  leucocytes  are  from 
71.5  per  cent,  to  84  per  cent.  Alimentary  glycosuria  after  the  beginning  of  th>Toidin 
medication  negative  (confer  Falta.  Xrd'burgh.  and  Xobel). 

X-rav:  The  sella  turcica  is  destro3-ed  to  the  extent  that  its  site  is  no  longer  sharply 


Fig.  48.  Fig.  49. 

Case  of  acromegaly  (Observation  XXXI). 

delimited  below  and  in  front;  it  has  given  place  to  a  cavity  about  the  size  of  a  chestnut. 
The  anterior  clinoid  processes  are  replaced  by  washed-out  bone  masses;  this  is  true  also  of 
the  greater  part  of  the  floor,  especially  anteriorly.  The  somewhat  enlarged  clivus  pro- 
jects forward  as  a  characteristically  nipple-shaped  mass. 

Lately  the  patient  has  developed  a  pronounced  cachexia.  To  this  are  added  slight 
signs  of  a  myxedema,  especially  a  cushion-like  thickening  of  the  backs  of  the  hands  and  of 
the  skin  of  the  supraclavicular  fossae.  The  pulse  rate  in  the  fever-free  intervals  (the 
patient  now  frequently  suffers  with  bronchopneumonias)  is  about  70;  the  blood-pressure 
(Gartner)  h'es  near  the  figure  70;  the  former  rather  frequent  diarrheas  now  occur  only  in 
single  isolated  attacks.  There  is  mostly  constipation.  The  circumference  of  the  throat, 
it  is  true,  has  indeed  increased,  but  a  myxedematous  thickening  of  the  soft  parts  may 
indeed  play  a  part  in  it. 


The  behavior  of  the  thyroid  gland  in  this  case  is  instructive.     We  are 
dealing  with  tj-pical  case  of  acromegaly,  which  for  a  long  time  has  shown  signs 


ACROMEGALY  259 

of  hyperthyroidism  (sweats,  tachycardia,  tremor,  sHght  exophthalmus, 
diarrhea,  etc.).  Later  with  the  development  of  a  cachexia,  symptoms  of 
hyperthyroidism  retrogress  more  and  more,  to  give  place  to  a  slight  thyroid 
insufficiency. 

The  regressive  changes  in  the  thyroid  gland  that  so  frequently  become 
established  in  the  later  stages  of  acromegaly  might  well  be  regarded  as  a 
partial  phenomena  of  the  degenerative  alterations  that  in  the  later  stages  of 
acromegaly  involve  not  only  these  organs  that  are  the  seat  of  the  tendency  to 
growth  fostered  by  the  acromegaly,  but  also  the  entire  body  as  well.  Hence 
in  the  later  stages  of  acromegaly  we  may  often  see  myxedematous  symptoms, 
even  in  the  absence  of  previous  manifestations  of  hyperthyrosis.  Pineles 
reports  two  cases  of  acromegaly  with  myxedema  of  the  skin,  stupidity,  and 
weakness  of  memory.  Improvement  of  the  myxedema  symptoms  followed 
the  administration  of  thyroid  gland,  although  they  were  not  influenced  by 
hypophysis  tablets. 

The  pathologico-anatomical  finding  in  the  thyroid  gland  in  acromegaly 
almost  always  shows  something  abnormal.  When  hyperthyrosis  has  existed, 
there  is  found  the  picture  of  a  Basedow's  struma.  Otherwise  there  is  seen 
almost  always  connective  tissue  proliferation,  such  as  is  found  also  in  other 
organs  in  acromegaly,  or  colloid  degeneration  in  combination  with,  eventually, 
high-grade  sclerosing  and  atrophy  of  the  parenchyma.  Gaussel  found  a 
thyroid  gland  that  was  normal. 

The  vascular  system  in  the  later  stages  of  acromegaly  almost  always  shows 
changes.  A  shght  grade  of  arteriosclerosis  develops.  Microscopical  examina- 
tion shows  that  the  three  vascular  coats  are  involved  in  these  changes,  and 
that  the  media  becomes  poor  in  muscle  fibers.  The  heart  not  infrequently 
hypertrophies,  and  the  cardiac  muscle  soon  degenerates.  Especially  those 
cases  that  are  attended  with  other  symptoms  of  Basedow's  disease  often 
show  in  the  initial  stages  a  slight  degree  of  tachycardia;  in  all  cases  manifesta- 
tions of  insufficiency  of  the  heart-muscle  develop  in  the  later  stages.  Varices 
are  strikingly  frequent. 

In  many  cases  the  enlargement  of  the  heart  may  very  well  be  a  partial 
manifestation  of  the  true  splanchnomegaly.  Humphry  describes  a  consider- 
able cardiac  hypertrophy  without  valvular  changes  in  a  man  aged  thirty-nine 
years.  The  case  reported  above  (Observation  XXIV)  there  was  a  broaden- 
ing of  the  cardiac  shadow,  on  X-ray  examination,  to  13  cm.  The  patient 
was  thirty-two  years  old.  Not  rarely  in  addition  to  the  enlargement  of  the 
heart  there  is  found  an  enlargement  of  the  liver,  the  spleen,  the  stomach, 
and  the  intestines.  The  enlargement  of  the  liver  is  often  only  the  sequel  of 
an  existing  cardiac  insufficiency,  sometimes,  however,  the  partial  manifesta- 
tion of  a  true  splanchnomegaly.  The  enlargement  of  the  spleen  is  a  partial 
manifestation  of  the  enlargement  of  the  lymphatic  apparatus  to  be  described 
later.     The  dilatation  of  the  stomach  has  been  brought  into  association  with 


2  6o  THE    DISEASES    OF    THE    HYPOPHYSIS 

the  frequently  observed  polyphagia.  Cunningham  describes,  in  a  case,  a 
doubhng  of  the  length  of  the  small  intestines.  Also  the  kidneys  are  often 
strikingly  large,  and  in  the  urine  a  shght  grade  of  albuminuria  is  not  infre- 
quently found.  In  two  cases  Fischer  found  enormous  suprarenals,  the  en- 
largement affected  especially  the  cortex;  also  Delille  saw  this  several  times. 
Lately  Fischer  and  Schidtze  found  enlargement  of  the  suprarenals  in  two  cases 
of  acromegaly,  in  one  of  which  (a  case  of  early  acromegaly)  the  suprarenals 
were  enlarged  about  five  times  at  least.  Histological  examination  showed 
that  the  suprarenals  in  toto  were  quite  uniformly  enlarged.  Also  the  kidneys 
were  enlarged,  showing  on  microscopical  examination  enormously  large 
glomeruli. 

In  many  cases  the  pancreas  was  found  to  be  sclerosed,  in  other  cases  the 
pancreas  was  found  to  have  been  entirely  normal  (see  later  the  combination  of 
acromegaly  and  diabetes) .  In  many  cases  of  acromegalic  gigantism  the  pan- 
creas were  of  quite  enormous  size  (up  to  270  gm.,  Launois  and  Roy).  A  per- 
sistent thymus  gland  in  acromegaly  was  already  found  by  Klehs  and  Fritsche. 
Since  their  time  this  finding  has  been  reported  very  frequently  (Dal ton, 
Arnold  and  others);  detailed  references  as  to  the  literature  can  be  found  in 
Borchardt  (Deutsches  Archiv  f  iir  khn.  Med.)  Pierre  Marie  regards  the  enlarge- 
ment of  the  thymus  as  a  reviviscence.  The  enlarged  thymus  may  pro- 
duce a  distinct  dullness  over  the  upper  half  of  the  sternum,  although  nothing 
should  be  concluded  as  to  the  enlargement  of  the  thymus  when  this  dullness 
is  found,  as  in  acromegalics  the  sternum  is  often  thickened  enormously. 

The  examination  of  the  hlood  in  acromegaly  shows  not  rarely  a  reduction 
in  the  number  of  erythrocytes  and  in  the  hemoglobin  contents.  This  was  ob- 
served by  Sabrazes  and  Bonnes.  MessedagUa  saw  it  in  seven  cases,  Rotky 
in  five  cases.  In  the  cases  reported  above,  the  case  Str  (Observation 
XXXI)  had  4,700.000  red  blood  cells,  70  per  cent,  hemoglobin;  the  case  Ta 
(Observation  XX\TI),  4,900,000  red  cells  and  82  per  cent,  hemoglobin; 
the  case  Ti  (Observation  XXV),  4,490,000  red  cells  and  95  per  cent,  hemo- 
globin; the  case  Bo  (Observation  XXVI)  5,210,000  red  cells  and  85  per 
cent,  hemoglobin.  Hence  it  seems  that  in  the  latter  stages  the  erythrocyte 
count  and  hemoglobin  contents  are  reduced. 

The  number  of  leucocytes  is  mostly  normal  (Rotky),  although  there  is 
often  found  a  somewhat  reduced  count.  In  my  cases  the  case  Ad  (Observa- 
tion XXVIII),  showed  9800;  case  Bo  (Observation  XXVI)  8840;  case  Ta 
(Observation  XXVII)  5600;  case  Un  (Observation  XXIV)  6240,  and  finally 
case  Str  (Observation  XXXI)  only  2900. 

In  the  majority  of  cases  the  difi'erential  count  shows  a  mononucleosis  and 
not  rarely  an  increase  in  the  number  of  eosinophils.  Sabrazes  and  Bonnes 
found  this  in  two  cases,  MessedagUa  in  seven  cases  (30-37.8  per  cent,  lym- 
phocytes), i?a//?y  in  five  cases;  Exner  in  one  case  found  39  per  cent,  mono- 
nuclear cells  and  61  per  cent,  eosinophiles.     Likewise  Franchini  and  GiglioH 


ACROMEGALY  261 

found  mononucleosis  in  four  cases,  and  among  these  hypereosinophilia  in 
two  cases.  Mendel  in  one  case  found  even  18  per  cent,  eosinophilia.  Also 
Messedaglia  and  Rathy  found  for  the  most  part  an  increase  in  the  eosinophiles. 
In  my  own  case  Ta  (Observation  XXVII)  showed  76  per  cent,  neutrophils 
and  2  per  cent,  eosinophiles;  case  Da  (Observation  XXVIII)  74  per  cent, 
neutrophiles  and  6  per  cent,  eosinophiles;  case  Bo  (Observation  XXVI) 
63.8  per  cent,  neutrophiles  and  2.3  per  cent,  eosinophiles;  case  Ad  (Obser- 
vation XXIX)  66  per  cent,  neutrophiles  and  i  per  cent,  eosinophiles;  case 
Str  (Observation  XXXI)  60  per  cent,  neutrophiles;  case  Un  (Observation 
XXIV)  57.6  per  cent,  neutrophiles  and  1.3  per  cent,  eosinophiles,  and  in 
case  Ti  (Observation  XXV)  56.7  per  cent,  neutrophiles  and  0.2  per  cent, 
eosinophiles. 

Lately  a  report  on  the  blood-findings  in  three  cases  has  been  contributed 
by  Borchardt.  He  found  the  erythrocytes  approaching  normal,  the  poly- 
morphonuclear neutrophiles  but  little  reduced,  the  eosinophiles  mostly 
increased. 

Hence  the  leucocyte  count  rather  frequently  shows,  especially  in  the  later 
stages,  a  relative  and  perhaps  also  an  absolute  reduction  in  the  number  of 
neutrophilic  cells,  and  a  relative  increase  in  the  large  mononuclears;  perhaps 
this  is  the  expression  of  a  more  or  less  well  pronounced  status  lymphaticus,  as 
has  been  found  in  several  autopsies.  {Messedaglia,  SchuUze,  Fischer,  Rothy, 
Claude  and  Baudouin,  et  al). 

The  anomalies  of  metabolism  in  acromegaly  need  a  very  exact  exposition. 
In  many  cases  there  exists  obesity,  as  in  the  much-quoted  case  of  Strumpell, 
although  this  was  reported  as  simply  "layer  of  fat  abundant."  Lately 
SchuUze  and  Fischer  have  reported  a  case  of  early  acromegaly  who  was  fat. 
Also  the  patient  in  Observation  XXIX  was  fat.  In  a  review  of  the  literature 
I  have  never  found  pronounced  obesity.  Frequently  there  exists  voracious 
hunger  and  polyphagia,  relatively  rarely  lasting  for  long  periods,  and  for  the 
greater  part  intermittent.  Whether  this  symptom  should  always  be  re- 
garded as  a  sign  of  hyperthyrosis,  or  whether  it  belongs  to  acromegaly  proper, 
I  shall  leave  unanswered. 

Observations  as  to  the  exchange  of  gases  in  acromegaly  have  been  carried 
out  only  by  Zantz-Gepperfs  apparatus  {Magnus -Levy,  H.  Salomon,  and  the 
recent  investigations  of  Bernstein  and  myself).  I  have  summarized  these  in- 
vestigations as  follows: 

The  investigations  concerning  the  respiratory  exchange  of  gases  made  up 
to  the  present  do  not  appear  to  decide  with  complete  certainty  the  question 
as  to  whether  in  acromegaly  there  occurs  an  increase  in  the  caloric  production 
that  may  be  ascribed  to  the  disease  as  such.  In  the  case  of  Magnus-Levy  the 
oxygen  consumption  and  the  production  of  carbonic  acid  doubtlessly  are 
appreciably  increased.  But  just  here,  according  to  the  statement  of  the 
authors,  there  were  present  symptoms  of  hyperthyrosis  that  were  not  appre- 


262 


THE    DISEASES    OF    THE    HYPOPHYSIS 


ciable.  In  case  i  of  Salomon  the  exchange  of  gases  is  not  appreciably  height- 
ened, in  proportion  to  the  size  and  body  weight  of  the  individual.  The 
slight  glycosuria  can  certainly  not  be  regarded  as  a  sign  of  increase  (confer 
later  on,  in  the  chapter  on  the  pancreas,  the  statements  as  to  the  exchange  of 
gases  in  diabetes  mellitus) .  Whether  the  sweats  that  occur  in  this  case  and 
the  voracious  hunger  that  occurred  from  time  to  time  are  to  be  referred  to  a 
hyperthyrosis  is  not  at  all  certain  in  itself. 


Author 

Sex  and 
age 

Height 
in  cm. 

Weight 

O2    need 
c.c.  per  k 
per  min. 

CO2  prodi 
tion  in  c 
per  kg.  p 
min. 

Remarks 

Magnus-Levy 

Salomon  case  i 

FS2 
M  49 

147 
183 

52.0 
112. 0 

4-9 

4-25 
4-33 

No  diabetes. 

Sick  for  about  19  years,  copi- 
ous sweats,  often  voracious 
hunger     and     increased     thirst. 

Potency    not    disturbed,     built 
on     herculean     lines,     diabetes 

(elimination    of    sugar    reaches 

Salomon  case  2 

F51 

160 

79.6 

4-3        3 ■ 04 

a  few  gm.). 

The  mother  is  also  sick  with 
acromegaly   and   diabetes.     For 
7  3'ears  alterations  in  face,  for  3 

years     great     thirst.     Diabetes 

Salomon  case  3 

Salomon  case  4 

M42 
F36 

158 
143 

79.6 
56.5 

3-96 
4.00 

304 
33 

gravis,  rather  fat. 

Sick  for  about  20  years,  no 
disturbance  of  potencj'. 

Amenorrhea  for  8  years,  no 
diabetes. 

Bernstein  and  Falta 

M31 

175 

89.0 

3-55 

2.73 

Strongly  built,  thyroid  slightly 
enlarged,  but  no  distinct  signs 
of  hyperthyrosis,  alimentary  gly- 
cosuria. 

Bernstein  and  Falta 

M32 

168 

750 

3-87 

3.16 

Thyroid  gland  enlarged,  slight 
signs  of  hyperthyrosis,   no  gly- 
cosuria on  overloading. 

In  case  2  the  consumption  of  oxygen  in  proportion  to  the  size  of  the 
patient  is  high.  But  there  exists  a  severe  diabetes.  Also  in  case  3  the 
oxygen  values  lie  somewhat  above  the  upper  limits  of  the  normal.  In  case 
4  the  exchange  seems  to  be  normal.  A  heightening  of  the  exchange  of  gases 
cannot  be  concluded  from  the  cases  reported  by  Bernstein  and  myself.  On 
the  whole  the  conclusion  that  Magnus-Levy  and  also  Salomon  have  arrived  at, 
namely,  that  in  uncomplicated  acromegaly  the  exchange  of  gases  is  not  in- 
creased is  correct.  In  the  later  stages  of  the  cachexia  and  the  decay,  the 
exchange  seems  to  be  rather  lower,  especiall>-  when  also  the  thyroid  gland 
degenerates  and  myxedematous  symptoms  are  added. 

Up  to  the  present  only  very  few  investigations  have  been  made  with  re- 
gard to  the  sail  metabolism.     Von  Moraczewski  found  in  a  case  of  acromegaly 


ACROMEGALY  263 

pronounced  retention  of  phosphorus,  calcium,  magnesium,  and  chlorine  (and 
also  nitrogen),  and  explains  this  by  the  increased  growth  of  the  tissue. 

Investigations  as  to  purin  metabolism  have  been  instituted  by  Nowaczinsky 
and  me  in  three  cases.  There  were  the  cases  already  described  as  case  T  (Ob- 
servation XXV),  U  (Observation  XXIV),  and  Ta  (Observation  XXVII). 
In  case  T  (thirty-one  years  old)  we  found  on  purin-free  diet  a  uric-acid  elimi- 
nation between  0.72  gm.  and  0.92  gm.  in  twenty-four  hours.  In  case  U 
(thirty- two  years  old)  between  0.89  gm.  and  1.16  gm.;  fourteen  days  after 
the  operation  still  higher  values  were  found.  As  has  already  been  men- 
tioned, in  this  case  the  operation  had  no  influence  on  the  acromegaly. 
After  the  administration  of  sodium  nucleinate  there  occurred  a  prompt 
increase  of  uric-acid  elimination.  In  case  Ta  (thirty-three  years)  there 
were  uric-acid  values  between  0.72  gm.  and  1.29  gm. 

Hence  in  all  three  cases  were  found  values  for  the  elimination  of  endogen- 
ous uric  acid  that  reached  the  double  or  more  than  the  double  of  the  endog- 
enous uric-acid  factor  observed  in  normal  individuals.  Any  complications 
can  hardly  be  regarded  as  the  cause  of  this  enormous  increase.  The  patients 
were  all  free  of  fever;  in  case  U  there  existed  very  slight  symptoms  of  hyper- 
thyrosis,  which  was  however  absent  in  both  other  cases.  Ta  had  had  lues, 
but  now  no  symptoms  of  lues  were  present.  Hence  we  must  assume  that  the 
increase  of  uric-acid  elimination  in  acromegaly  occurs  as  such,  the  more  so 
because  in  some  cases  of  hypophysial  dystrophia  adipiso-genitalis  we  find 
strikingly  low  endogenous  uric-acid  values.  In  one  case  of  acromegaly  there 
occurred  after  the  administration  of  purin-free  material  a  prompt  increase  in 
the  elimination  of  uric  acid,  while  in  the  cases  of  hypophysial  dystrophy  the 
elimination  of  uric  acid  was  extraordinarily  reduced. 

Such  high  values  for  the  endogenous  uric-acid  elimination  as  we  found  in 
three  cases  of  acromegaly  have  as  yet  been  observed  only  in  diseases  in  which 
much  lymphatic  tissue  is  destroyed,  or  in  certain  febrile  processes  attended 
with  marked  hyperleucocytosis  (acute  articular  rheumatism).  In  the 
cases  of  acromegaly  the  leucocyte  counts  were  rather  lower  than  normal. 
There  was  no  ground  whatever  for  the  assumption  of  an  increased  melting 
down  of  lymphatic  tissue.  Further  investigations  as  to  this  question  are 
very  desirable  (see  Chapter  I). 

Lately  Dr.  Vias  has  examined  a  quite  chronically  progressive  case  of 
acromegaly,  and  has  observed  no  increase  in  the  endogenous  uric-acid 
elimination. 

Quite  especially  frequent  is  acromegaly  complicated  with  glycosuria  or 
with  diabetes  mellitus.  Already  Pierre  Marie  had  stated  that  in  a  third  or  a 
half  of  the  cases  of  acromegaly  glycosuria  was  found.  Detailed  references 
to  the  literature  are  to  be  found  in  the  articles  of  Launois,  and  Roy  and  of 
Borchardt. 

Borchardt  collects  from  the  literature  176  cases  of  acromegaly  in  which 


264  THE    DISEASES    OF    THE    HYPOPHYSIS 

there  exist  specific  statements  as  to  the  examination  of  the  urine.  In 
sixty- three  cases,  that  is  35.5  per  cent.,  diabetes  was  found;  in  eight  cases 
alimentary  glycosuria.  In  many  cases  the  diabetes  shows  the  ordinary  course 
and  eventually  leads  to  death  in  coma.  In  many  cases,  however,  as  v. 
Noorden  first  emphasized,  the  glycosuria  shows  a  striking  independence 
from  the  sugar-value  of  the  diet.     The  cases  reported  by  me  behaved  thus: 

Observation  XXIV. — U,  on  diet  rich  in  carbohydrates neg. 

A'A'T'. — T,  alimentary  glycosuria  (100) pos. 

XXVI. — Bo  (distinct  hyperthyrosis  from  thyroidin) neg. 

XXVII. — Ta,  alimentary  glycosuria  also  on  diet  remarkably  rich  in 

carbohydrates strongly  pos. 

XXVIII. — Da,  alimentary  glycosuria pos. 

XXIX. — Ad,  alimentary  glycosuria pos. 

XXX. — St,  alimentary  glycosuria  (also  from  levulose) pos. 

XXXI. — Str,  at  first  alimentary  glycosuria pos. 

then  later,  on  many  investigations neg. 

Of  eight  cases,  five  were  distinctly  positive,  and  one  for  a  time  weakly 
positive.     In  one  case  (Ta)  we  may  even  speak  of  a  very  light  diabetes. 

The  behavior  toward  adrenalin  was  tested  in  two  cases  (Observation  St 
and  Observation  Ta)  with  negative  results. 

In  many  cases  alimentary  glycosuria  or  diabetes  occurs  only  in  the  initial 
stages  of  acromegaly;  later  these  cases  show  a  marked  tolerance.  W. 
Schlesinger  and  Borchardt  each  report  such  a  case.  Lately  also  Cushing  has 
reported  about  such  cases.  In  the  case  of  Borchardt  the  diabetes  had  existed 
five  years;  and  later  there  occurred  no  glycosuria  on  the  injection  of  150  gm.  of 
grape-sugar.  It  should  be  mentioned  that  not  rarely  such  diabetic  disturb- 
ances of  metabolism  occur  in  Basedow's  disease  (thyrogenic  glycosuria). 

In  the  few  cases  in  which  I  examined  the  excitability  of  the  vegetative 
nerves  showed  a  very  diverse  behavior.  In  the  case  Ta  there  occurred,  after 
the  injection  of  adrenahn,  marked  rise  of  blood-pressure,  tachycardia  and 
arrhythmia.  There  also  occurred  marked  diuresis,  but  not  glycosuria.  As 
in  this  case  sugar  appeared  in  the  urine  after  overloading  with  carbohydrates, 
it  stands  as  a  fine  example  of  the  independence  of  the  alimentary  and  the 
nervous  factors  {Falta,  Xcicburgli,  and  Xobel,  Case  43).  Also  the  in- 
jection of  pituitrinum  infundibulare  acted  as  a  marked  diuretic.  After 
the  injection  of  pilocarpine  there  occurred  only  moderate  sweats  and  a 
moderate  flow  of  sahva;  although  the  patient  stated  that  she  suffered  with 
crises  of  copious  sweats.  In  other  cases  the  action  of  pilocarpine  on  the  ex- 
citability of  the  sweat  glands  was  more  distinct.  Hence  there  may  occur 
temporary  conditions  of  marked  irritability  of  the  sweat  glands,  without 
hyperexcitability  of  them  existing  during  the  interval.  The  outbreaks  of 
sweat  are  known  to  be  a  very  common  symptom  of  acromegaly.  Magnus- 
Levy  and  Salomon  in  their  cases  of  acromegaly  regard  the  sweats  as  the  symp- 


ACROMEGALY  265 

torn  of  hyperthyrosis;  however,  it  seems  to  me  certain  that  the  outbreaks 
depend  on  another  cause  lying  in  the  nature  of  acromegaly  itself,  for  we  see 
them  also  in  the  cases  in  which  other  symptoms  of  Basedow's  disease — above 
all,  the  cardinal  symptom  of  the  hyperthyrosis,  the  tachycardia- — are  absent. 
This  was  the  case,  for  instance,  in  case  Ti  (Observation  XXV) . 

The  polyuria  may  also  be  looked  upon  as  dependent  on  an  abnormal 
condition  of  excitability  of  the  vegetative  nerves.  This  also  usually  occurs 
only  temporarily,  in  crises.  The  specific  gravity  of  the  urine  may  sink  in 
these  attacks  to  very  low  values,  reminding  us  of  a  true  diabetes  insipidus. 
As  I  have  mentioned  before,  there  may  exist  in  many  cases  an  especial 
sensitivity  of  the  nerves  of  the  kidney  for  adrenalin  or  for  pituitrinum  in- 
fundibulare.  It  is  not  clear  how  far  such  changes  in  the  condition  of  ex- 
citability of  certain  vegetative  nerves  may  be  brought  into  relationship  with 
functional  alteration  of  the  hypophysis.  At  most  we  may  conjecture  that 
the  critic  polyuria  may  be  associated  mth  temporary  irritation  of  the  posterior 
lobe  and  with  the  increased  production  of  hypophysial  "diuretin.'' 

The  fact  that  compHcation  with  hyperthyrosis  or  hypothyrosis  influences 
the  condition  of  excitabihty  of  the  vegetative  nerves  in  many  ways  needs  no 
further  consideration  in  detail. 

Very  often  the  pathologico-anatomical  examination  in  advanced  cases, 
shows  proliferation  of  the  connective-tissue  elements  in  the  vegetative  nerves 
and  ganglia  {Marie  and  Marinescu). 

The  symptoms  on  the  part  of  the  somatic  nervous  system  are  very  manifold. 
To  the  early  symptoms  often  belong  the  very  burdensome  rheumatoid  pains 
and  eventually  acroparesthesias  {Sternberg).  In  many  cases  the  pains 
occur  during  night,  so  that  the  patient  must  get  up  and  walk  around  the 
room  (Observation  XXIV) .  Also  sensation  of  heat  in  the  fingers  may  occur. 
In  one  case  there  occurred  transitory  swelling  of  the  finger-joints  simul- 
taneously with  the  pains.  Whether  combinations  with  continued  articular 
swellings  and  chronic  deforming  processes  in  the  joints,  as  was  present  in 
Str,  Observation  XXXI,  are  common,  I  have  not  been  able  to  glean  from  the 
literature.  The  behavior  of  the  reflexes  varies.  Sometimes  they  are  in- 
creased, sometimes  reduced. 

Also  alterations  of  the  mind  and  intelligence  occur  in  acromegaly.  In 
many  cases  there  exists  a  characteristic  apathy,  a  want  of  initiative,  and  a 
slowing  of  the  speech.  In  rare  cases,  conditions  of  exaltation  are  observed. 
The  pathologico-anatomical  examination  of  the  nervous  system  shows  no 
constant  findings;  except  that  in  the  later  stages  there  occurs  regularly  an 
increase  of  the  connective-tissue  elements  in  the  nerves. 

Among  the  symptoms  of  acromegaly  there  is  still  a  group  that  has 
nothing  to  do  with  the  disease  process  in  itself  but  is  produced  mechanically 
by  the  enlargement  of  the  hypophysis.  To  these  belong  first  of  all  the  changes 
in  the  sella  turcica;  Oppenheim  was  the  first  to  recognize  enlargement  of 


266  THE    DISEASES    OF    THE    HYPOPHYSIS 

the  sella  during  life  by  means  of  the  X-rays.  Since  that  time  X-ray  technique 
has  improved  wonderfully  and  has  become  of  important  diagnostic  aid. 
The  changes  in  the  sella  may  be  very  different;  frequently  when  the  tumor 
is  situated  purely  intrasellarly  there  exists  a  widening  out  of  the  sella  with 
deepening  of  the  floor.  This  may  bring  the  bony  partition  between  sella 
and  sphenoidal  sinuses  to  paper-like  thinness  or  to  actual  perforation;  even 
when  the  tumors  are  large  the  clinoid  processes  may  remain  intact.  In 
very  large  tumors  too,  however,  there  may  be  a  widening  of  the  entrance  to  the 
sella  and  final  destruction  of  the  clinoid  processes.  The  tumor  may  also 
calcify.     Calcifications  of  the  dura  are  not  rare. 

The  following  X-ray  finding  in  a  typical  case  of  acromegaly  serves  as  an 
example : 

Observation  XXXII. — U,  Dec.  g.  The  sella  turcica  is  not  only  widened  on  the  whole 
to  twice  its  size  (measured  in  the  sagittal  direction)  but  also  is  very  roomy  at  its  introitus. 
This  also  is  at  least  double  as  wide  as  normal.  The  floor  of  the  sella  turcica  has  its  homo- 
geneous rotundity  infringed  upon,  and  is  polygonal  with  washed-out  borders.  Several 
crumbly  calcareous  masses  in  the  interior  of  the  sella  may  well  be  supposed  to  be  calcified 
tumor-masses.     The  widening  that  is  here  present  shows  itself  in  a  sharpening  at  its  base. 

The  lack  of  an  enlargement  of  the  sella  does  not  militate  against  acro- 
megaly. On  the  one  hand,  as  we  shall  see  later,  there  may  be  present  specific 
microscopical  alterations  also  in  hypophyses  that  are  scarcely  enlarged, 
especially  in  the  initial  stages  of  the  disease;  and  on  the  other  hand  there 
may  be  present  a  tumor  of  the  hypophysis  in  the  sphenoidal  sinuses  pro- 
ceeding from  epithelial  rests  of  the  hypophysial  duct,  or  such  a  tumor  of 
the  hypophysis  of  the  pharyngeal  vault.  In  the  first  case  the  floor  of  the 
sella  may  be  even  eroded  from  below,  and  thus  the  connection  with  the  hypo- 
physis be  established  secondarily  (Erd/ieim). 

Later,  in  the  consideration  of  the  tumors  of  hypophysis,  we  shall  come 
back  to  the  subject  of  the  differential  diagnostic  significance  of  the  altera- 
tions of  the  sella. 

To  the  symptoms  called  into  existence  by  the  pressure  of  the  growing 
tumor  belong  also  headache,  and  eventually  dizziness  and  vomiting.  But 
the  last  two  symptoms  as  well  as  paresis  of  the  cranial  nerves  are  relatively 
rare  in  this  disease. 

On  the  contrary  there  are  found  more  frequently  disturbances  on  the 
part  of  the  optic  nerves,  disturbances  not  rarely  in  the  form  of  bitemporal 
hemianopsia  and  hemianopic  pupillary  reaction;  the  latter  according  to 
researches  of  Wernicke  and  of  Dcjcrine  almost  surely  indicate  a  hypophysial 
tumor. 

In  addition  to  the  hemianopsia  there  is  found,  also  commonly,  simple 
amblyopia;  these  manifestations  may  occur  unilaterally.  They  can  lead  to 
blindness  of  one  or  both  eyes;  examination  of  the  eye-grounds  shows  for  the 
most  part  alterations  of  the  papillae  in  the  sense  of  a  neuritis  (in  40  per  cent.) 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS  267 

or  of  an  atrophy,  rarely  choked  disc.  I  shall  return  to  the  manifestations  of 
brain-pressure  in  the  consideration  of  the  subject  of  nonacromegahc  hypo- 
physial tumors. 

Pathological  Anatomy  of  the  Hypophysis 

I  now  turn  to  the  treatment  of  the  nature  of  the  hypophysial  tumors  in 
acromegaly.  Although  this  subject  is  the  most  important,  I  have  placed  it  at 
the  end  of  the  long  series  of  symptoms,  because  it  acts  as  transition  to  the 
subject  of  the  pathogenesis  of  the  disease.  To-day  we  may  state  with  great 
probability  that  in  every  typical  case  of  acromegaly  there  exist  in  the 
anterior  lobe  of  the  hypophysis  adenomata  or  adenocarcinomata,  which  in 
rare  cases  are  dystopic,  proceeding  from  cut-off  hypophysial  cells.  The 
questions  on  this  subject  that  have  been  energetically  discussed  during  the 
last  decade  are :  Are  there  cases  of  acromegaly  mthout  hypophysial  tumor, 
or  without  the  adenomatous  changes  in  the  hypophysis  regarded  as  specific; 
and,  are  there  cases  of  such  tumors  that  do  not  show  any  of  the  symptoms  of 
acromegaly?  These  questions  have  recently  been  discussed  with  tempera- 
ment in  a  monograph  by  B.  Fischer;  I  shall  refer  the  reader  to  the  literature 
on  the  subject  and  shaU  attempt  here  only  to  bring  to  the  front  the  principal 
opinions  on  this  subject. 

Hanau  first  pointed  out  that  in  the  overwhelming  majority  of  cases  of 
acromegaly,  adenoma  of  the  hypophysis  was  observed.  Through  the  dis- 
covery of  a  specific  coloration  for  the  cell  granules  in  the  chromophilic 
cells  by  Benda  the  recognition  of  the  adenomatous  tumors  has  become  es- 
sentially easier.  Benda  himself  found  in  three  of  four  cases  of  acromegaly  the 
cell  granules  in  monstrous  excess  in  the  adenomatously  degenerated  anterior 
lobe  of  the  hypophysis.  For  most  part  the  forms  of  adenoma  are  benign.  In 
the  malignant  form,  which  does  occur,  and  in  which  growth  is  very  rapid,  the 
cells  may  remain  very  small.  In  such  cases  under  circumstances  the  presence 
of  these  among  the  gland-cells  can  be  determined  only  by  the  use  of  Benda' s 
stain.  Such  malignant  adenomata  were  for  the  most  part  formerly  regarded 
as  carcinomata.  Fischer  says  that  the  other  kinds  of  tumors,  such  as  carcino- 
mata,  sarcomata,  endotheliomata,  etc.,  never  produce  acromegaly;  this  state- 
ment seems  to  be  correct  except  that  the  position  of  the  cases  of  typical  acro- 
megaly in  which  the  pathological  finding  points  to  adenocarcinoma.  I  refer 
to  the  case  of  Cagnetto.  Cagnetto  described  a  large  adenocarcinoma  ^\ith 
abundant  secretion  granules,  proceeding  from  the  glandular  part  of  the 
hypophysis,  which  led  to  metastases  in  the  spinal  cord;  in  these  metastases 
the  chromophilic  cells  were  demonstrable.  Fig.  50,  for  which  I  am  indebted 
to  Prof.  Stoerck,  shows  a  similar  case.  The  hypophysis  is  in  this  respect 
analogous  to  the  thyroid  gland,  in  which  adenocarcinomata  associated  with 
metastases  and  manifestations  of  Basedow's  disease  are  described.  If  in 
cases  with  mahgnant  degeneration  of  the  adenomata  of  the  hypophysis  the 


268  THE    DISEASES    OF    THE    HYPOPHYSIS 

chromophilic  cells  are  sometimes  very  few,  this  would  not  militate  against 
the  applicabihty  of  the  above-mentioned  postulate,^  as  in  malignant  tumor 
there  frequently  sets  in  an  anaplasia  of  the  cells,  as  Fischer  correctly  points 
out.  Again  cases  of  acromegaly  have  been  described,  in  which  the  sec- 
tions indeed  disclosed  tumors  proceeding  from  the  glandular  part  of  the 
hypophysis,  which  tumors,  however,  were  cystically  degenerated,  and 
showed  but  very  httle  glandular  tissue.  Here  it  is  indeed  remarkable  how 
rapidly  after  extirpation  of  the  part  of  the  tumor,  in  the  cases  thus  far  operated 
on,  the  manifestations  of  acromegaly  ameliorate.  These  cases,  however, 
are  fresh  ones;  in  very  old  cases  with  acromegaly  they  perhaps  would  not 


•  V  *  s  L  it'  L*- ,  V*» .  •  =  •  •"'  ";r^ 


*?'♦    "* 


s^iiy' 


^ 


Fig.  so. — Adenocarcinoma   of   the   hypophysis   made  up,  in  great  part,  of  eosinophilic   cells. 

ameliorate  so  rapidly.  Finally  the  cases  with  colloid  struma  of  the  hypo- 
physis have  been  brought  as  evidence  against  the  postulate,  in  that  in 
acromegaly  such  strumas  may  be  found  without  proper  adenomatous  forma- 
tion, and  on  the  other  hand  there  may  be  found  typical  strumas  with  small 
adenomata  without  acromegaly.  As  example  of  the  first  t>pe  I  mention 
the  case  of  Widal,  Roy,  and  Froin.  Here  there  existed  typical  acromegaly 
in  a  sixty-six-year-old  man,  and  atrophy  and  sclerosis  of  the  gland  substance 
which  was  permeated  with  colloid  cysts;  in  spite  of  the  atrophy  there  could  be 
found  rather  numerous  chromophilic  cells.  As  example  of  the  second  type 
I  refer  to  the  cases  of  Zack  and  Cagnetto.     The  case  of  Cagnetto  was  that  of  a 

^  i.  e.,  that  in  everj^  typical  case  of  acromegaly  the  anterior  lobe  of  the   hypoph\-sis  shows 
adenoma  or  adenocarcinoma. — Editor. 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS   ^         269 

thirty- two-year-old  woman  without  acromegaly;  the  hypophysis  weighed 
1.55  gm.  which  is  thrice  the  normal  weight;  microscopically  was  found  a 
typical  struma,  in  which  small  adenomatous  portions  alternated  with 
strumous  portions.  The  analogous  relation  with  the  thyroid  furnishes  a 
key  in  this  case.  There  are  also  cases  of  Basedow's  disease  in  which  only 
"Basedow's  islands"  are  to  be  found  in  the  thyroids. 

Pathogenesis.^ — Already  Pierre  Marie  had  recognized  the  connection  of 
acromegaly  with  the  hypophysis;  at  all  events  he  supposed  that  the  tumor 
destroyed  the  functionating  pituitary  tissue,  v.  Strumpell,  Arnold  and  others 
advocated  the  opinion  that  enlargement  of  the  hypophysis  was  coordinated 
with  that  of  the  acral  parts,  in  other  words  that  it  is  only  a  partial  phenome- 
non of  a  general  disturbance  of  metabolism  (endogenous  theory).  The 
theory  of  hyperfunction  was  first  upheld  by  Tamburini,  Benda,  and  Massa- 
longo.  Other  authors  have  supposed  a  primary  disturbance  of  function  of 
the  sexual  glands  {Freund,  Verstraeten,  Stumme,  lately  E.  Mayer,  especially) . 

Finally  the  endogenous  theory  has  been  modified  by  other  authors 
{Claude,  Delille)  in  that  they  regard  acromegaly  as  a  pluriglandular  affection. 

The  assumption  of  a  loss  of  function  of  the  hypophysis  in  acromegaly 
can  at  the  present  day  no  longer  be  regarded  as  correct.  We  shall  see  later 
that  processes  that  destroy  the  glandular  hypophysis  never  lead  to  acro- 
megalic symptoms,  but  to  symptoms  of  an  entirely  different  kind.  The 
same  thing  occurs  in  animals  after  the  hypophysis  has  been  extirpated.  The 
supposition  of  a  primary  functional  disturbance  of  the  sexual  glands  is  no 
longer  tenable,  in  that,  as  we  shall  see  later,  there  are  cases  of  acromegaly  in 
which  the  sexual  glands  still  functionate,  even  although  the  disease  has  been 
fully  developed  for  several  years.  Against  the  endogenous  theory,  speaks, 
among  other  facts,  the  results  of  the  partial  extirpation  of  the  tumor  of  the 
hypophysis,  as  will  be  dealt  with  more  in  detail  later.  This  places  the 
hypophysis  as  the  central  figure  of  the  pathogenesis  of  acromegaly.  That 
in  acromegaly  other  ductless  glands  are  involved  very  frequently  was  already 
mentioned  by  Pineles,  which  fact,  as  we  have  seen,  makes  the  disease  picture 
very  manifold.  The  circumstance  that  this  involvement  is  a  very  diverse 
one,  that,  for  example,  at  one  time  there  occurs  on  the  part  of  the  thyroid 
symptoms  of  hyperfunction  and  at  another  time  symptoms  of  those  of 
insufficiency  shows  once  more  the  predominating  position  of  the  hypo- 
physis. Hence  only  those  manifestations  may  be  regarded  as  cardinal 
symptoms  of  acromegaly,  which  are  to  be  referred  directly  to  the  altera- 
tion of  the  hypophysis;  there  are  in  addition  to  these  a  herd  of  secondary 
symptoms. 

Besides  the  results  of  the  surgical  treatment  it  is  especially  the  similarity 
of  the  pathologico-anatomical  findings  in  the  hypophysis  in  acromegaly 
with  those  of  the  thyroid  in  Basedow's  disease  that  indicate  that  acromegaly 
is  brought  about  through  an  increase  in  the  Junction  of  the  glandular  hypophysis. 


270  THE    DISEASES    OF    THE    HYPOPHYSIS 

Against  this  assumption  there  has  been  objected  that  in  many  cases  as 
above  mentioned,  there  are  found  strumas  of  the  glandular  hypophysis  in 
which  degenerative  manifestations  predominate,  and  that  on  the  other  hand 
the  strumas  or  small  adenomata  occur  without  acromegaly.  I  beheve  that 
the  dictum  of  Kocher  that  there  are  strumas  and  strumas  holds  for  the  h>^o- 
physis  as  well  as  for  the  thyroid.  To-day  no  one  would  be  surprised  that, 
especially  in  the  old  Basedow's  cases,  parts  of  the  thyroid  are  degenerated, 
and  that  on  the  other  hand  small  adenomata  of  the  thyroid  gland  are  often 
unattended  with  any  of  the  manifestations  of  Basedow's  disease.  The 
morphological  finding  does  not  always  indicate  the  functional  condition. 
Finally  should  be  mentioned  that  in  rare  cases  of  acromegaly  entirely  normal 
h}'pophyses  are  found.  In  many  of  these  cases  the  diagnosis  of  acromegaly 
is  doubtful  (syringomyela,  congenital  abnormal  size  of  the  acra,  etc.^).  In 
other  cases  we  find  dystopic  adenomata  of  the  h}'pophysis  which  proceed 
from  cut-off  cells  [versprengte  Keime]  {Erdheim  and  Haherfeld). 

I  have  already  referred  several  times  to  the  manifold  analogies  that  exist 
between  the  lesion  of  the  thyroid  gland  and  those  of  the  hypophysis.  As 
we  shall  see  later  the  assumption  that  hypophysial  dystrophia  adiposo- 
genitaKs  depends  on  a  lessened  function  of  the  h}'pophysis  is  based  on  ex- 
perimental pathology  in  a  fashion  analogous  to  that  in  which  the  assumption 
of  myxedema  is  a  hypothyrosis  has  been  demonstrated  by  experiment. 
On  the  contrary  the  conditions  for  acromegaly  are  to-day  very  much  more 
unfavorable  than  those  for  Basedow's  disease.  The  most  important  support 
for  the  theory  that  it  depends  on  a  hyperfunction  of  the  hypophysis  lies,  as 
I  have  mentioned  previously,  in  the  results  of  the  surgical  treatment  of 
acromegaly.  Reduction  in  the  size  of  the  h>'pophysis  through  extirpation 
of  portion  of  the  gland  leads  in  many  cases  to  a  retrogression  of  the  acromeg- 
alic manifestations.  That  this  is  not  true  in  all  cases,  for  example,  in  the 
case  of  U  (Observation  XXIV),  does  not  seem  to  me  of  great  significance, 
as  on  account  of  the  shght  visibility  of  the  field  of  operation,  we  do  not  know 
anything  as  to  the  size  and  value  of  the  piece  of  tumor  left  behind.  In 
analogy  with  experiences  in  Basedow's  disease  it  is  very  probable  that  a 
result  could  have  been  obtained  by  a  further  reduction  of  the  tumor. 

On  the  contrary,  the  attempts  to  produce  a  hyperfunction  of  the  h>T)o- 
physis  experiments  have  hitherto  been  attended  with  very  sHght  results. 
The  stimulating  [fordernd]  influence  of  the  hypophysis  on  the  growth  as 
inferred  from  the  clinical  observations,  has  as  yet  not  been  demonstrated 

^  Also  tall  eunuchoids  have  been  confused  with  acromegalics.  Thus  for  instance  we  find 
described  hy  Gallais  a.  case  of  "gigantisme  acromegalique  sans  elargissement  de  la  seUe  turcique" 
with  "inversion  sexuelle  and  feminisme  mental."  In  this  case  quite  sudden  rapid  growth  started 
at  fourteen  and  one-half  j'ears  of  age,  that  was  also  present  to  lesser  degree  in  the  twenty-fifth 
year.  Hands  and  feet  were  very  long  and  slender.  In  the  illustration  that  accompanies  the 
report  of  the  case  absolutely  nothing  of  acromegaly  is  to  be  seen.  It  shows  however  typical 
eunuchoid  obesity. 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS  27 1 

experimentally  with  certainty.  The  attempt  to  feed  growing  animals 
with  hypophysis  substance  seems  to  me  not  to  have  furnished  convincing 
results  as  yet.  Worthy  of  note  in  this  regard  are  the  statements  of  Exner 
that  implantation  of  several  hypophyses  hastened  the  growth  of  young  rats. 

The  investigations  with  injection  of  pituitary  extracts  have  indeed  led 
to  recognition  that  the  latter  possess  not  inappreciable  physiological  actions, 
but,  nevertheless,  we  have  not  been  able  to  bring  them  into  relation  with 
the  pathogenesis  of  acromegaly  with  such  certainty  as  is  the  case  in  analo- 
gous experiments  in  Basedow's  disease.  It  is  to  be  regarded  as  established, 
however,  that  the  physiological  actions  of  the  extracts  from  the  anterior 
lobe  are  quite  other  than  those  of  extracts  of  the  pars  intermedia  and  pos- 
terior lobe.     Let  us  first  consider  the  action  of  the  latter. 

The  extract  from  the  pars  intermedia  and  posterior  lobe,  that  has  been 
made  entirely  free  of  albumin,  has  in  many  respects  actions  similar  to 
adrenalin,  without  however  giving  the  color  reactions  of  adrenalin.  The 
extract  from  the  entire  hypophysis  acts  as  a  blood-pressure-raising  agent 
and  a  pulse-slowing  agent  by  contraction  of  the  peripheral  vessels  (Oliver 
and  Schdjer).  Howell  later  found  that  this  action  is  due  solely  to  the  ex- 
tract of  the  infundibular  part.  The  initial  lowering  of  blood-pressure  that  is 
sometimes  observed,  may  be  referred  to  the  admixture  with  other  substances, 
perhaps  with  those  which  are  identical  with  what  are  found  in  large  amounts 
in  the  glandular  extract.  These  can  be  separated  from  the  other  by  ex- 
traction with  alcohol.  The  blood-raising  action  of  pituitrinum  infundibulare 
distinguishes  from  that  of  adrenalin  in  that  it  often  remains  absent  on  short 
spaced  repetition  of  the  injections.  The  vasoconstrictor  action  can,  in  man, 
be  very  readily  shown.  After  subcutaneous  injection  of  i  to  2  cc.  we  mostly 
find  a  distinctly  pronounced  local  ischemia  that  often  lasts  longer  than  an 
hour.  Subcutaneous  injection  of  so  small  an  amount  raises  the  blood-pres- 
sure, in  man,  for  a  long  time  after  the  injection.  Also  it  produces  mydriasis 
of  the  isolated  ball  of  a  frog's  eye.  Further  it  acts  as  a  strong  diuretic  {Mag- 
nus and  Schdjer)  by  a  dilatation  of  the  renal  vessels  (Haliburton) ;  according  to 
Pal  only  the  peripheral  section  of  the  renal  artery  dilates,  while  the  proximal 
part  contracts.  The  different  vascular  distributions  behave  especially 
diversely  to  the  action  of  the  drug.  The  diuresis  may  be,  in  man,  very  con- 
siderable; in  case  Ta,  Observation  XXVII,  we  saw  an  increase  in  the  amount 
of  twenty-four-hour  urine  from  800  cc.  to  1200  cc.  According  to  Kepinow 
pituitrinum  infundibulare  sensitizes  the  points  of  attack  of  adrenalin.  The 
actions  of  pituitrinum  infundibulare  thus  far  detailed  have,  with  the  exception 
of  the  slowing  of  the  pulse,  all  adjusted  to  the  irritation  of  the  sympathetic 
nerves.  It  also  acts,  however,  on  certain  organs  supplied  by  autonomous 
nerves  in  the  sense  of  a  stimulation  through  the  autonomous  nerves.  While 
according  to  Frankl-Hochwart  and  Frdhlich  the  autonomous  vagal  cardiac,  the 
nerves  of  the  pancreas,  the  chorda  tympani,  and  the  nervi  erigentes  are  not 


272  THE    DISEASES    OF    THE    HYPOPHYSIS 

influenced  as  to  their  excitability,  the  excitability  of  the  nerves  of  the  urinary 
bladder  and  the  musculature  of  the  uterus  are  markedly  heightened,  or  the 
uterine  musculature  is  brought  to  strong  contraction.  This  action,  according 
to  the  experiments  of  Fleming  and  myself  may  be  set  aside  through  the  use 
of  atropine.  It  is  only  constant  in  the  gravid  uterus,  while  in  the  virginal 
uterus  there  may  even  occur  inhibition  of  the  peristaltic  waves.  Also  cer- 
tain chemotactic  actions  (mononucleosis,  hypereosinophilia)  are  perhaps  to 
be  referred  to  the  irritation  of  autonomous  nerves.  According  to  Ott  and 
Scott,  and  Schajer  and  Mackenzie,  the  extract  of  the  posterior  lobe  contains 
galactogogue  substances. 

Also  the  actions  on  the  metabolism  are  very  appreciable.  Schijf  after 
feeding  a  case  of  acromegaly  saw  with  hypophysis  tablets  a  16  per  cent, 
increase  of  ehmination  of  phosphorus,  in  a  case  of  paralysis  a  25  per  cent, 
increase.  The  increase  principally  affected  the  elimination  through  the 
feces.  According  to  our  investigations  (Bolaffio  and  Tedesco)  this  action 
is  to  be  referred  to  the  pituitrinum  infundibulare,  as  we  saw  appreciable 
increase  in  the  elimination  of  phosphorus  after  its  injection.  That  a  large 
part  of  the  phosphorus  is  ehminated  through  the  feces  finds  its  explanation 
in  the  fact  that  also  the  calcium  elimination  through  the  feces  is  much  in- 
creased, and  the  calcium  travels  with  the  phosphorus  in  the  intestine.  We 
also  found  an  appreciable  increase  in  elimination  of  nitrogen  in  fasting  dogs 
and  in  those  in  whom  the  nitrogen  metabolism  was  in  equilibrium.  In  a  case 
of  acromegaly  to  whom  he  administered  hypophysis  tablets,  v.  Moraczewski 
found  an  increase  in  the  elimination  of  nitrogen,  but  not  in  that  of  calcium. 

Cushing  recently  states  that,  according  to  his  investigations,  extracts 
from  the  posterior  lobe  of  the  hypophysis  or  from  the  pars  intermedia,  also 
possess  an  action  on  carbohydrate  metabolism.  Intravenous  injection  of 
posterior  lobe  extracts  into  a  rabbit  always  produces  glycosuria.  Further- 
more, subcutaneous  or  intravenous  injection  of  extract  of  posterior  lobes  re- 
duce the  tolerance  limits  for  carbohydrates  even  in  animals  with  heightened 
tolerance  limits  in  which  the  hypophysis  had  been  removed.  Bernstein  and  / 
could  not  corroborate  Gushing' s  statement  in  experiments  that  we  instituted, 
using  the  otherwise  active  pituitrin  of  Parke,  Davis  is°  Co.  First,  on  the  in- 
jection of  large  quantities  (up  to  33  cc.)  to  rabbits  and  dogs,  we  never  saw  the 
appearance  of  glycosuria.  Nor,  according  to  earUer  experiments  of  Priestley 
and  myself  is  there  an  increase  in  the  blood  sugar-contents.  Second,  in 
experiments  on  man  we  have  never  been  able  to  influence  [by  its  use]  the 
tolerance  Hmits  for  carbohydrates.  After  the  injection  of  pituitrinum  in- 
fundibulare (up  to  3  cc.)  we  never  saw  the  occurrence  of  alimentary  gly- 
cosuria on  the  administration  of  100  gm.  dextrose,  and  in  individuals  who 
already  had  alimentary  glycosuria,  this  was  never  increased  under  the 
influence  of  pituitrinum  infundibulare.  Nor  did  we  see  an  increase  in 
the  ehmination  of  sugar  in  diabetics.     Especially  important  seem  to  me  the 


PATHOLOGICAL    ANATOMY    OF    THE    HYPOPHYSIS  273 

experiments  on  diabetics  who  at  the  time  were  sugar-free.  Here  if  the 
tolerance  hmits  for  sugar  were  reduced  as  a  result  of  the  injection,  we  would 
expect  to  see  a  recurrence  of  the  sugar.  Finally  in  respiratory  experiments  on 
men  there  occurred  regularly  after  the  injection  of  pituitrinum,  an  increase 
in  the  production  of  carbonic  acid  or  of  consumption  of  oxygen,  but  never 
a  distinct  rise  of  the  respiratory  quotient. 

As  example  I  cite  the  following  experiment:    Case  Ti  (Acromegaly) 

Date  CO2  O2              RQ 

February  14 257.5  342 -o  0.753 

February  16 247.7  329. S  0.748 

40  min.  after  the  injection  of  2  cc.  pit.  inf 297.0  393-9  0.754 

Whether  the  investigation  was  made  a  short  or  a  long  time  after  the  in- 
jection, there  could  never  be  observed  a  distinct  rise  of  the  respiratory  quo- 
tients. The  increase  in  the  respiratory  metabolism  that  we  found  after 
the  injection  of  pituitrinum  infundibulare  may  very  well  be  referred  to  an 
increased  stimulation  of  smooth-muscled  organs  probably  also  to  an  in- 
creased activity  of  the  liver.  At  least  the  hyperemia  of  the  liver  that 
E.  Neubauer  found  in  oncometric  experiments  seems  to  point  that  way. 

Miller  and  Dean  Lewis  state  that  intravenous  or  intraperitoneal  injec- 
tions of  extracts  of  posterior  (and  anterior)  lobes  of  the  hypophysis  in  dogs 
indeed  may  sometimes  induce  transitory,  very  weak,  glycosuria;  it  is  here 
very  questionable,  however,  whether  this  has  anything  to  do  with  the  in- 
ternal secretion  of  the  hypophysis. 

The  extract  of  the  glandular  portion  of  the  hypophysis  was  formerly 
regarded  as  entirely  without  action.  Ivkovic  and  /  found,  however,  that  one 
of  the  extracts  furnished  to  us  for  trial  by  the  firm  of  Parke,  Davis  &  Co. 
possessed  a  pronounced  depressor  action;  after  the  intravenous  injection  of 
2  to  3  cc.  of  this  extract  there  occurred  a  depression  of  the  blood-pressure, 
which  latterly  again  returned  spontaneously  to  the  normal;  previous  ad- 
ministration of  atropine  would  not  hasten  this  return  to  normal,  but  on  the 
contrary  would  retard  it.  When  large  doses  of  the  extracts  were  used,  in 
two  of  our  experiments  the  blood-pressure  sank  to  zero,  and  there  was 
cessation  of  respiratory  and  cardiac  action;  in  one  of  these  experiments  the 
heart  could  be  made  to  beat  again  by  administration  of  pituitrinum  in- 
fundibulare; the  blood-pressure  gradually  rose  to  normal  again,  and  the 
animal  entirely  recovered.  Later  Hamburger  without  knowing  about  our 
experiments,  likewise  reported  concerning  the  depressor  action  of  the  ex- 
tract of  the  glandular  hypophysis.  In  numerous  experiments  that  Bern- 
stein and  /  made  on  human  beings  since  that  time  we  could  never  demonstrate 
a  distinct  sinking  of  blood-pressure  after  the  subcutaneous  or  intravenous  in- 
jection of  several  cubic  centimeters  of  this  extract.  Hence  the  dog  seems 
very  much  more  sensitive  in  this  direction.  We  did  observe  in  human  beings, 
however,  an  extremely  striking  action.  Shortly  after  the  injection  of  a 
iS 


0. 

RQ 

327-9 

0.780 

246 . 96 

0-935 

274  THE    DISEASES    OF    THE    HYPOPHYSIS 

slight  amount  of  the  extract — often  2  cc.  intramuscularly  was  sufficient — 
the  production  of  CO2  and  the  consumption  of  oxygen  were  reduced.  At 
the  same  time  the  respiratory  quotient  rose  appreciably.  This  rise  in  the 
respiratory  quotient  lasts  in  man  for  thirty  to  forty-live  minutes,  then 
it  gradualh'  sinks  to  the  normal,  while  ordinarily  the  lowering  of  the  total 
respiratory  exchange  of  gases  lasts  much  longer. 

I  cite  the  following  experiment  as  an  example:     Case  Ti  (Acromegaly) 

Date  CO2 

February  23 256 .  i 

One-half  hour  after  intravascular  injection  of  pit.  gl. .      230.77 

In  experiments  on  a  dog  we  found  that  on  much  longer  doses  (up  to 
30  cc.)  the  lowering  of  the  respiratory  exchange  of  gases  was  much  the  less 
distinctly  pronounced,  and  that  the  rise  in  the  respiratory  quotient  also  was 
not  so  well  expressed  as  in  man. 

The  extract  used  is  albumin-free,  but  often  gives  a  biuret  reaction.  The 
slight  amounts  of  albumoses  present  could  not  cause  the  depressor  actions 
that  we  observed,  as  the  action  occurred  just  as  promptly  after  the  albumoses 
were  removed.  Also  the  chloretone  employed  with  the  extract  furnished  to 
us  could  not  account  for  this  action.  Finally  it  could  be  shown  that  the 
active  principle  is  not  cholin,  as  the  depressor  action  on  the  blood-pressure 
continued  after  the  previous  administration  of  atropine. 

The  interpretation  of  these  results  is  attended  w4th  great  difhculties. 
The  circumstance  that  we  were  not  able  to  observe  a  depressor  action  in 
man  does  not  signify  very  much.  It  is  possible  that  also  here  a  dilatation 
of  the  vessels  occurs,  but  the  action  of  this  on  the  blood-pressure  is  neutral- 
ized by  counter-regulations.  The  depressor  action  on  the  exchange  of  gases 
would  let  it  be  supposed  that  temporarily  the  tonus  of  organs  with  smooth 
musculature  or  that  the  activity  of  the  great  glands  of  the  body  is  reduced.^ 
Still  harder  to  explain  is  the  action  on  the  respiratory  quotient.  We 
originally  thought  that  the  extract  called  for  a  mobilizing  or  increased  com- 
bustion of  the  carbohydrates,  and  that  on  account  of  this  there  occurred  also 
a  reduction  in  the  total  combustion.  But  in  experiments  on  two  severe  dia- 
betics it  was  shown  that  here  also  there  occurred  a  lowering  of  the  respiratory 
metabolism,  but  here  the  respiratory  quotient  remained  quite  unaffected. 
The  experiments  also  speak  against  the  objection  that  the  rise  in  the  respira- 
tory quotients  has  its  foundation  in  an  alteration  in  mechanism  of  breathing. 
Further  it  was  shown  in  numerous  experiments  that  were  constantly  modi- 
fied, that  this  extract  does  not  act  as  a  glycosuretic,  and  does  not  essentially 
influence  an  existing  alimentary  glycosuria.  Exceptions  perhaps  are  certain 
experiments  on  diabetics  on  whom  after  institution  on  a  very  low  elimi- 

1  E.  Neubauer  was  so  kind  as  to  make  a  oncometric  experiment  on  the  liver  of  rabbits.     He 
found  after  injection  of  pituitrinum  glandulare  distinct  reduction  of  the  liver  volume. 


PATHOLOGICAL    ANATOMY    OF    THE    HYPOPHYSIS  275 

nation  of  sugar,  there  several  times  occurred  a  slight  increase  in  the  glycosuria 
after  injection.  Finally,  however,  it  was  shown  that  after  the  injection  of 
this  extract  there  was  never  observed  either  in  experiments  on  man  or  on 
dogs,  an  increase  of  the  blood  sugar-contents,  but  on  the  contrary  there 
was  a  decrease.  Borchardt  saw  the  occurrence  of  glycosuria  after  the  in- 
jection of  hypophysis  extract  in  the  rabbit.  In  dogs  for  the  most  part  this 
was  wanting.  According  to  our  experiment  I  would  not  estimate  very 
highly  the  value  of  the  evidence  of  the  experiments  on  the  rabbit.  After 
all  that  I  have  said  thus  far  as  to  the  action  of  the  extract  of  the  glandular 
part  of  the  hypophysis,  it  may  well  be  assumed  that  the  latter  in  some  manner 
involves  the  carbohydrate  metabolism,  not,  however,  by  mobilizing  carbo- 
hydrates in  the  liver,  but  rather  by  an  increase  of  the  combustion  of  the 
sugar  in  the  periphery.  With  this  agrees  very  well  the  decrease  in  the 
blood  sugar.  I  am  fully  aware,  however,  that  this  is  nothing  more  than  a 
hypothesis. 

If  we  consider  once  more  the  individual  physiological  actions  that  have 
thus  far  been  demonstrated  for  the  glandular  or  the  infundibular  extract  of 
the  hypothesis,  we  readily  see  that  they  furnish  very  little  information  for 
the  pathogenesis  of  acromegaly.  The  function  of  the  cardiovascular  ap- 
paratus is  ordinarily  not  altered  in  acromegaly  in  a  striking  manner,  if 
manifestations  of  hyperthyrosis  or  hypothyrosis  are  not  present  at  the  same 
time. 

Closest  lies  the  idea  that  the  polyuria  sometimes  observed  may  be 
referred  to  a  temporary  irritation  of  the  posterior  lobe  through  the  growing 
adenoma  of  the  anterior  lobe.  This  conception  may  explain  the  fact  that 
such  polyurias  also  frequently  occur  in  tumors  of  the  hypophysis  of  other 
sorts,  that  are  associated  not  with  phenomena  of  hyperfunction  of  the  hypo- 
physis but  on  the  contrary  with  those  of  insufhciency  (see  later) .  As  far  as 
the  genital  disturbances  in  acromegaly  are  concerned,  the  described  action 
of  the  infundibular  extract  on  the  genital  organs  has  not  as  yet  helped  to 
make  them  more  intelligible.  In  acromegaly  we  find,  as  has  been  stated  in 
detail  before,  rather  an  increased  activity  of  the  interstitial  glands,  and  even- 
tually, after  transitory  increase  of  function,  setting  aside  of  the  functions 
of  the  sexual  glands.  In  hypophysial  dystrophy  there  exists  a  severe  dys- 
trophy of  the  genital  organs  that  includes  also  the  interstitial  glands.  It  is 
therefore  very  much  more  likely  that  these  alterations  of  the  genital  function 
rather  stand  in  correlation  with  alterations  in  the  function  of  the  glandular 
hypophysis.  Nothing  at  all  is  thus  far  known,  however,  as  to  the  action  of 
the  glandular  extract  on  the  sexual  glands.  The  respiratory  exchange  of 
gases  does  not  tend  to  become  altered  in  acromegaly,  at  least  as  far  as  there 
exist  no  complications  with  hyperthyrosis,  and  in  dystrophia  adiposo-geni- 
talis  it  is,  as  we  shall  see  later,  perhaps  sometimes  reduced.  The  depressor 
action  of  the  glandular  extract  and  the  furthering  action  of  the  infundibular 


276  THE    DISEASES    OF    THE    HYPOPHYSIS 

extract  can  hardly  be  called  upon  to  explain  this  disease  picture.  Also  the 
explanation  of  the  disturbance  of  carbohydrate  metaboKsm  so  commonly  ob- 
served in  acromegaly  seems  to  me  to  encounter  unsurmountable  obstacles. 

Rath  and  later  Loeb  supposed  that  in  acromegaly  the  tumor  of  the  hypo- 
physis pressed  on  a  neighboring  sugar  center;  the  diabetes  in  acromegaly 
would  thus  be  placed  in  analogy  to  the  glycosuria  sometimes  occurring  in 
?.poplexv.  This  view  has  recently  been  adopted  by  Aschner.  This  author 
succeeded  in  demonstrating  that  a  sympathetic  center  lies  in  the  subthalmic 
region,  the  irritation  of  which  causes  glycosuria.  The  glycosuria  does  not 
occur  after  transection  of  the  splanchnic  nerves  and  therefore  like  that  of 
Claude-Bernard's  piqure  goes  over  the  chromaffin  tissue.  In  spite  of  the 
convincing  experiment  of  Aschner,  I  cannot  agree  with  his  conclusion;  it  is 
not  clear  to  me  why  just  in  acromegaly,  a  developing  hypophysis  tumor 
should  press  on  this  center,  while  the  tumors  of  the  hypophysis  without 
acromegaly,  that  often  lie  in  the  h>'pophysial  duct  or  even  extrasellary,  and 
that  give  occasion  to  symptoms  of  great  brain  pressure,  produce  no  diabetes; 
in  these  cases,  on  the  contrary,  as  we  shall  see  later,  the  tolerance  limits 
for  carbohydrates  are  practically  always  appreciably  raised. 

Pineles  supposes  a  correlative  affection  of  the  pancreas.  Actually 
Hansemann  and  Dallemagne  have  found  atrophy  of  the  pancreas  in  acro- 
megalic diabetes.  It  is  indeed  very  probable  that  in  the  cases  of  acromegaly 
combined  wdth  severe  diabetes  the  pancreatic  genesis  stands  in  the  fore- 
ground. We  see  in  acromegaly  degenerative  changes  in  almost  all  the  organs 
occur  simultaneously  with  or  in  the  course  of  the  period  of  increased  tendency 
for  growth,  and  the  insular  apparatus  may  rapidly  become  involved  in  the 
process,  just  as  are  involved  the  sensitive  glands  of  generation. 

Schlesinger  assumes  in  acromegaly  not  only  the  occurrence  of  a  true 
pancreatic  diabetes  but  also  of  a  brain-tumor  diabetes.  Lorand  is  of  the 
opinion  that  the  glycosuria  of  acromegaly  is  thyrogenic  as  a  result  of  the 
relationship  of  the  hypophysis  to  the  thyroid  gland.  The  views  may  be 
very  well  true  for  a  part  of  the  cases,  namely,  that  part  in  which  distinct  mani- 
festations of  the  hyperthyrosis  are  present.  How  shall  we  explain,  however, 
the  inclination  of  alimentary  glycosuria  or  even  a  spontaneous  glycosuria 
in  these  cases  in  which,  as  in  case  Ti  (Observation  XXV)  the  hyperthyrosis 
is  entirely  absent,  quite  apart  from  the  cases  with  severe  diabetes  or  diabetes 
leading  to  coma?  Xaunyn  and  later  Borchardt  regard  the  diabetes  in  acro- 
megaly as  directly  hypophysial,  that  is  brought  about  through  the  production 
of  an  agent  that  induces  glycosuria.  The  view  seems  to  me  to  have  a 
certain  support  in  the  repeatedly  mentioned  investigations  of  Bernstein  and 
myself.  I  have  previously  stated  in  detail  that  the  glandular  extract  some- 
how seems  to  enter  in  the  regulation  of  the  carbohydrate  metabolism,  but 
I  am  not  in  the  position  to  say  anything  exact  about  this  action.  We  are 
thus  evidently  guided  by  opinions,  and  I  would  like  to  be  understood  as 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS  277 

believing  that  in  the  majority  of  cases  a  premature  degeneration  of  the 
insular  apparatus  seems  the  most  likely  explanation. 

Pathological  physiology  has  as  yet  furnished  with  very  little  for  the 
understanding  of  the  pathogenesis  of  acromegaly.  As  yet  just  the  most 
important  symptoms,  the  increased  tendency  for  growth  of  a  certain  part  of 
the  organism,  especially  the  osseous  system,  have  not  been  reproduced  ex- 
perimentally. In  spite  of  this  the  supposition  of  a  hyperfunction  of  the 
hypophysis  in  acromegaly  is  to-day  the  only  satisfactory  one. 

For  this  assumption  speaks: 

1.  The  opposition  of  the  clinical  pictures  of  acromegaly  and  hypophysial 
dystrophy. 

2.  The  fact  that  the  latter  may  be  produced  by    extirpation    of   the 
hypophysis. 

3.  The  results  of  surgical  interference. 

4.  The  analogy  with  affections  of  the  thyroid  gland. 

Early  Acromegaly. — The  statements  thus  far  set  forth  as  to  the  patho- 
genesis of  acromegaly  are  concerned  with  the  clinical  picture  that  we  meet 
with  in  adults.  Acromegaly  indeed  develops  almost  exclusively  after  the 
twentieth  year.  We  must  now  consider  the  important  question  as  to  whether 
there  exists  an  acromegaly  of  child  or  adolescent  life,  and  whether  the  picture 
of  early  acromegaly  deviates  from  that  of  adults.  Brissaud,  Sind  Launois  and 
Roy  adopt  the  view  that  hyperfunction  of  a  hypophysis  in  early  youth  before 
the  closure  of  the  epiphysial  juncture  leads  to  gigantism  and  after  the  definite 
ending  of  growth  to  acromegaly.  According  to  this  view  all  pathological 
gigantism  would  then  be  acromegaly.  This  view  was  already  vigorously 
opposed  by  Pierre  Marie.  I  shall  deal  with  this  question  later  in  the  chapter 
on  gigantism,  and  only  would  remark  here,  that  I  also  cannot  subscribe 
to  this  view,  as  may  be  plainly  seen  on  the  perusal  of  the  following  details. 
I  believe  much  more  that  there  exists  an  early  acromegaly  with  gigantism; 
only  it  seems  that  this  condition  is  relatively  very  rare,  and  is  much  more 
manifold  as  to  its  symptomatology  than  is  the  typical  acromegaly  of  adults. 

It  here  seems  to  me  necessary  to  enter  more  in  detail  concerning  the  re- 
ports on  this  subject  that  occur  in  the  literature.  Most  intelligible  is  a  group 
of  cases  in  which  the  clinical  picture  is  very  similar  to  the  acromegaly  of 
adults.  To  this  group  belongs  the  case  described  by  Arnold  as  early  as  1891. 
According  to  the  definite  statement  of  the  author  the  acromegalic  manifesta- 
tions in  this  patient  began  to  develop  distinctly  in  the  eighteenth  year  of  life. 
In  a  brother  of  the  patient,  who  also  suffered  from  acromegaly,  the  be- 
ginning of  the  aft'ection  came  on  at  a  still  earlier  period  of  life.  There  is 
no  doubt  at  all  that  this  case  was  one  of  acromegaly;  this  was  shown  by  the 
typical  thickening  of  the  bones  that  increased  in  intensity  toward  the 
periphery.  Also  the  exact  microscopical  examination  of  the  bones  showed 
architecture  typical  for  acromegaly.     In  the  muscles,  in  the  peripheral  nerves, 


278  THE    DISEASES    OF    THE    HYPOPHYSIS 

the  vessels,  and  the  weak  parts,  there  may  everywhere  be  found  hyperplasia 
of  the  connective  tissue.  It  is  worthy  of  note  in  this  case  that  the  sella 
turcica  was  not  essentially  widened,  and  that  further  there  was  a  markedly 
developed  hairiness,  especially  of  the  extremities.  Hence  although  in  this 
case  the  beginning  of  the  affection  occurred  at  the  time  at  which  normally 
the  epiphyses  are  not  as  yet  closed,  increase  in  height  was  not  present  in 
this  case.  In  this  respect  it  seems  to  me  significant  that  there  were  not 
eunuchoid  manifestations  in  this  case;  on  the  contrary,  as  was  evinced  by 
the  hairiness,  rather  was  there  an  accentuation  of  the  function  of  the  inter- 
stitial glands. 

A  case  of  Claude's  shows  that  in  acromegaly  the  closure  of  the  epiphysial 
junctures  may  occur  prematurely.  It  was  that  of  a  girl  nineteen  years  old  in 
whom  the  acromegalic  manifestations  had  gradually  developed  since  the 
fifteenth  yesir.  The  epiphysial  junctures  were  completely  closed,  and  there 
was  no  tendency  to  abnormal  height. 

Very  important  is  the  case  recently  reported  by  Schulize  and  Fischer. 
Here  the  disease  began  at  the  eleventh  year  of  life.  Since  that  time  had  ex- 
isted headache,  vomitings,  and  temporary  salivations.  The  patient  had 
never  menstruated.  In  the  course  of  three  days  she  became  blind  and 
almost  deaf  (probably  on  account  of  narrowing  of  the  inner  ear  on  account  of 
osseous  thickening). 

The  girl  was  167  cm.  tall,  weighed  81.5  kg.  At  various  places  there 
were  pronounced  pigmentations,  the  skin  of  the  entire  body  was  rather  dark, 
from  the  navel  there  was  marked  development  of  the  hair  in  the  middle  line, 
also  hair  on  the  upper  lip.  At  various  places  dark  nevi.  Inclination  for 
sweats.  Head  very  long,  horizontal  circumference  59  cm.  Upper  lip  mark- 
edly cushioned,  nose  thick.  Tongue  enormously  thickened,  alimentary 
glycosuria  negative.  Bilateral  choked  disc  and  atrophy.  Death  manifestly 
due  to  cerebral  pressure.  Pronounced  obesity.  Thymus  h}^erplastic. 
General  splanchnomegaly.  Also  the  liver,  kidneys,  and  especially  the 
suprarenal  glands  greatly  enlarged  (the  last  to  five  times  their  size) .  Uterus 
small,  infantile  cysts  of  the  ovaries,  no  formation  of  follicles.  The  tumor 
of  the  h}TDophysis  was  of  abnormal  size  (6.5  to  4.5  cm.).  ^Microscopically 
t^^pical  adenoma  rich  in  cells. 

SchuJtze  and  Fischer  regard  this  case  as  a  mixed  form  between  an  ordi- 
nary t}'pical  acromegaly  and  dystrophia  adiposo-genitalis. 

Another  type  is  found  by  the  case  described  by  PeL  a  type  that  I  herewith 
describe  in  detail.  The  case  was  that  of  a  sLxteen-year-old  youth.  Since  birth 
the  size  of  the  hands  and  feet  had  been  strikingly  large  and  they  gradually 
increased  in  growth;  especially  of  late,  after  a  febrile  affection,  they  have  be- 
come of  enormous  dimensions.  In  this  increase  in  size  the  increase  in  the 
dimensions  of  the  individual  bones  of  the  extremities  at  the  distal  parts  was 
quite  extraordinary.     Thus  the  forearms  were  29  cm.  long,  the  circumfer- 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS  279 

ences  of  the  elbows  about  27  cm.,  the  middle  finger  about  11  cm.  long,  the 
thumbs  7-7}^  cm.,  the  circumference  of  the  knee  40-41  cm.,  the  length  of 
the  feet  about  31  cm.,  the  left  leg  weighed  4.85  kg.,  the  right  5.1  kg.  With  all 
this  the  total  height  of  the  body  was  not  very  great  (172  cm.).  The  body 
weight  was  50  kg.  The  head  was  small,  only  the  nose  and  the  tabular  part 
of  the  occipital  bone  were  somewhat  larger;  the  teeth,  especially  the  upper 
incisors,  were  strikingly  large.  The  dimensions  were  eunuchoid  (lower 
length  112  cm.),  the  genital  organs  were  entirely  infantile  (penis  5  cm.), 
the  secondary  sexual  characters  were  not  developed.  X-ray  examination 
showed  that  the  sella  turcica  was  widened,  and  that  only  the  body  parts  of 
the  extremities  were  so  considerably  enlarged.  From  youth  on  there  had 
existed  pains  of  a  lancinating  character;  lately  there  were  very  profuse 
sweats,  great  muscular  weakness,  and  sensitiveness  of  the  periosteum  of 
the  long  bones  to  pressure.  It  is  further  noteworthy  that  veins  of  the  en- 
larged parts  were  markedly  dilated.  A  nearly  analogous  case  was  recently 
observed  in  the  Hochenegg  clinic  and  was  exhibited  by  Demmer  before  the 
Gesellschaft  der  Arzte  in  Vienna  [Vienna  Medical  Society].  Pel  termed 
this  case  "acromegalic  partielle  avec  infantilisme." 

Another  type  is  described  by  Babonneix.  The  case  was  that  of  a  seventeen- 
year-old  epileptic,  174  cm.  tall,  two  years  ago  gradual  beginning  of  abnormal 
growth  of  the  extremities.  The  hands  became  strikingly  long,  the  feet 
"laughably"  voluminous,  this  together  with  alteration  of  the  disposition, 
polyphagia  and  polydipsia;  pubic  hairs  sufficiently  developed,  genitalia 
strikingly  well  developed,  especially  the  penis  and  testicles,  the  frontal 
sinuses  remarkably  large,  eye-grounds  normal,  sella  turcica  not  enlarged. 
Babonneix  speaks  of  an  acromegaliform  syndrome.  A  similar  case  was 
exhibited  by  Mosse  before  the  Societe  de  neurologic  of  Paris  in  May,  19 11. 

Still  another  type  is  described  by  Renon  and  Delille.  A  sixteen-and-one- 
half-year-old  girl,  who  was  normal  up  to  the  sixteenth  year  of  life,  became 
affected  with  eye-disturbances,  headaches  and  backaches  with  vomiting, 
increased  growth.  Now  168  cm.  tall  (lower  length  103  cm.,  span  width  180 
cm.)  outbreaks  of  sweat,  obesity  especially  in  the  loins  and  on  the  abdomen, 
breasts  poorly  developed  (fat  is  painful).  Slight  hairiness  of  the  pubic 
region  and  axillae.  Has  not  as  yet  menstruated,  sella  turcica  much  enlarged, 
optic  atrophy.     The  authors  regard  this  case  as  a  polyglandular  disturbance. 

Finally  there  are  reports  as  to  the  occurrence  of  acromegaly  in  early 
childhood.  Salle  reports  the  following:  The  nose  of  a  new-born  infant  was 
strikingly  large,  the  chin  prominent,  the  auricles  large,  flap-like,  the  tongue 
large.  The  relation  of  the  extremities  and  of  the  head  to  the  total  length  was 
that  of  a  two-year-old  child.  Hands  and  feet  especially  large,  fingers  and  toes 
strikingly  large.  Ossification  corresponds  to  that  of  a  three-  to  four-year-old 
child.  The  child  died  at  the  age  of  two  and  one-half  months.  The  sella 
turcica  was  very  large,  the  hypophysis  was  deformed  in  the  shape  of  a  bean 


28o  THE    DISEASES    OF    THE    HYPOPHYSIS 

through  the  projection  of  an  exostosis  into  the  sella  turcica;  it  was  as  large 
as  that  of  an  adult,  the  enlargement  affected  especially  the  glandular  part. 
Microscopically  was  found  a  very  considerable  richness  in  eosinophilic  cells, 
such  as  is  found  in  adults  but  not  in  children.^ 

Finally  Hutinel  describes  a  case  with  enlargement  of  the  acra  in  a  thirteen- 
and-one-half-year-old  boy. 

The  cases  set  forth  suffice  to  indicate  the  great  multiplicity  of  the  forms 
of  early  acromegaly.  In  one  is  found  a  large  tumor  of  the  hypophysis,  in 
the  others  the  sella  turcica  is  not  at  all  abnormally  large;  but  despite  this 
latter  fact  I  would  not  doubt  that  in  these  cases  {Arnold,  Pel,  Demmer,  etc.) 
the  diagnosis  acromegaly  is  certain  or  at  least  hardly  doubtful.  Further, 
the  deformation  of  the  bones  is  also  very  varied.  A  manifestation  that  ap- 
parently may  occur  in  early  acromegaly  in  an  especially  well-marked  manner, 
is  the  entirely  irrelative  increase  in  size  of  the  bones  of  the  extremities  in  a 
distal  direction.  Very  diverse,  too,  is  the  proportioning,  in  that  in  many  cases 
the  eunuchoid  proportion  is  very  prominently  in  the  foreground;  then 
again  the  condition  of  the  genitalia  is  very  different  too;  in  some  cases  there 
is  hyperplasia,  in  others  hypoplasia  and  faulty  development  of  the  secondary 
sexual  characters,  even  association  with  eunuchoid  obesity;  then,  as  in  the 
case  of  Schultze  and  Fischer,  hypoplasia  of  the  genitaha  and  obesity,  but 
marked  hairiness  (hyperplasia  of  the  suprarenals). 

The  cause  of  this  great  multiplicity  of  type  can  perhaps  be  seen  in  the 
fact  that  the  child  organism  or  the  ductless  glandular  apparatus  of  children 
reacts  to  a  hyperfunction  of  the  hypophysis  in  a  very  much  more  diverse 
manner  than  that  of  adults.  Especially  the  developing  genital  glands  that 
are  involved  can  behave  differently,  in  that  here  the  interstitial  glands  may 
be  damaged  and  thus  may  bring  to  the  total  picture  admixture  with  features 
of  eunuchoidism.  Then  again,  dependent  to  a  large  extent  on  the  behavior 
of  the  genital  glands  is  the  premature,  normal,  or  delayed  closure  of  the 
epiphysial  junctures.  Also  the  dimensioning  of  the  body  may  be  influenced 
on  account  of  this.  I  would,  however,  treat  of  one  point  with  emphasis.  In 
some  cases  the  diagnosis  may  very  well  be  doubted,  in  fact  in  some  cases  it  is 
even  made  by  the  respective  authors  with  reserve.  In  other  cases,  however, 
there  is  no  room  for  doubt;  and  we  must  reckon  with  the  fact  that  acromegalic 
alterations  in  the  extremities  may  occur  also  in  youth,  and  that  therefore 
the  hyperfunction  of  the  hypophysis  in  early  youth  does  not  necessarily  lead  to 
gigantism. 

Differential  Diagnosis. — The  point  of  difficulty  in  the  diagnosis  of 
acromegaly  lies  in  the  disproportionate  growth  of  the  peripheral  parts,  not 
in  the  enlargement  itself,  as  this  may  be  congenital.     There  is  found  for  in- 

1  Also  Benda  (Med.  Klin.,  191 2,  284)  regards  the  histological  alterations  as  typical,  but  does 
not  regard  the  fact  ruled  out  that  the  alterations  of  the  jaws,  tongue,  and  hands,  may  simply 
have  been  inherited. 


PATHOLOGICAL  ANATOMY  OF  THE  HYPOPHYSIS  281 

stance  a  cranium  progeneum  in  many  other  conditions  that  have  nothing  to 
do  with  acromegaly  {Sternberg) .  Confusion  with  osteitis  deformans  of  Paget 
is  hardly  likely  on  careful  examination.  In  osteitis  deformans  the  cranium 
is  enlarged  chiefly  in  circumference,  the  long  bones  soon  show  curvatures, 
the  alterations  in  the  skeleton  are  very  asymmetrical.  In  osteoarthropathie 
hypertrophiante  pneumonique  the  skull  remains  unaltered,  only  the  nose  may 
be  larger.  In  this  condition  we  have  a  dorsolumbal  kyphosis,  in  acromegaly 
a  cervicodorsal  kyphosis;  the  end  phalanges  show  the  well-known  drumstick 
form,  the  nails  show  curving  and  longitudinal  ridges;  while  chiefly  the  region  of 
the  knuckles  is  very  much  swollen  up,  the  metacarpal  and  metatarsal  region, 
as  Souza  Leithe  points  out,  show  but  shght  increase  in  volume.  Under  cir- 
cumstances there  may  occur  in  the  osteoarthropathy  club-like  swelhngs  of  the 
hands  and  feet,  that  may  have  given  occasion  to  confusion  with  acromegaly 
(confer  the  case  of  Schultz  and  Fischer).  Combination  with  symptoms  of 
Basedow's  disease  or  myxedema  may  in  the  beginning  occasion  an  overlooking 
of  the  acromegaly.  Early  genital  disturbances  or  rheumatoid  pains  may 
lead  to  a  faulty  diagnosis.  Syringomyelia  may  also  lead  to  an  increase  in 
volume  of  the  extremities,  but  in  this  condition  there  are  usually  found  in 
addition  deformations  and  the  well-known  dissociation  of  the  sensation- 
qualities.  In  ordinary  macrosomia  only  single  members  are  affected,  never 
both  upper  extremities  and  both  lower  extremities  simultaneously.  Cases 
in  which  hands  and  feet  were  enormously  enlarged  I  have  already  discussed 
in  the  consideration  of  early  acromegaly  {Pel,  Demmer) .  We  must  not  for- 
get that  the  acra  of  the  face  may  begin  to  become  enlarged  very  much 
later.  Erb  saw  such  a  case;  the  enlargement  of  the  extremities  had  existed 
for  about  twenty  years  before  the  tongue  and  nose  began  to  enlarge. 

Finally  we  must  refer  to  the  significance  of  the  demonstration  of  the 
enlargement  of  the  sella  turcica  by  Rontgen  transillumination,  as  first  demon- 
strated by  Oppenheim. 

In  acromegaly  there  is  usually  found  deepening  of  the  floor  of  the  sella 
without  material  widening  of  the  introitus,  while  in  the  tumors  of  the 
hypophysis  without  acromegaly  dilatation  of  the  introitus  and  destruction 
of  the  clinoid  process  is  commoner,  although  there  are  exceptions. 

Important  for  a  differential-diagnostic  standpoint  is,  finally,  the  cir- 
cumstance that  genital  disturbances  may  occur.  Salbey  reports  a  case  in 
which  oophorectomy  was  undertaken  because  of  amenorrhea  and  pains  in 
the  back  and  abdomen.  Several  months  later  there  developed  a  picture  of 
acromegaly. 

Until  lately  the  treatment  was  utterly  ineffective.  Striking  results  were 
first  brought  about  by  the  resection  of  the  hypophysis  tumor  first  inaugu- 
rated by  Horsley,  by  Schlojfer,  and  by  t).  Eiselsberg  and  first  happily  carried  out 
by  Hochenegg.  I  refer  to  the  consideration  of  hypophysial  dystrophy  for 
a  discussion  of  the  method  of  operation.     In  the  first  two  cases  of  Hochenegg 


282  THE    DISEASES    OF    THE    HYPOPHYSIS 

(reported  by  Stumme  and  Exner)  there  occurred  not  only  a  disappearance  of 
the  symptoms  of  cerebral  pressure  but  also  a  retrogression  of  the  acromegaly 
manifestations  as  well.  The  teeth  of  the  upper  jaw  again  approached  each 
other,  the  acra  became  smaller,  the  skin  softer  and  wrinkly,  the  menses  re- 
turned, and  the  abnormal  hairiness  again  retrogressed;  the  retrogression  of 
the  acromegalic  skeletal  alterations  could  also  be  denoonstrated  by  the  X-ray 
{Hochenegg).  In  two  cases,  Exner  saw  an  enlargement  of  the  thyroid  set  in 
after  the  operation.  Since  this  time  a  number  of  other  operated  cases  have 
been  reported,  in  part  with  good  results  (v.  Eiselsberg.  Kocher,  Moskovitz, 
Lecene,  Gushing,  O.  Hirsch,  and  others).  Especially  striking  was  the  result  in 
the  case  of  O.  Hirsch,  in  which  rheumatoid  pains  disappeared,  the  acra  de- 
creased in  size,  and  the  menses  recurred  and  since  that  time  remained  regular. 
Hochenegg.  on  the  basis  of  a  third  case  that  pursued  an  unfavorable  course, 
points  out  that  in  cases  in  which  the  tumor  is  chiefly  extrasellar  the  chances 
of  operation  are  always  very  much  less.  Considerable  destruction  of  the 
clinoid  processes  and  shght  deepening  of  the  floor  of  the  sella  must,  like 
myodegeneratio  cordis  and  status  lymphaticus,  be  taken  in  consideration 
when  the  question  of  operation  arises. 

I  refer  again  to  the  cases  already  described  in  detail  that  were  operated 
on  by  O.  Hirsch.  In  one  there  came  about  an  essential  subjective  and  ob- 
jective improvement.  In  the  other  case,  which  I  saw  again  after  a  half 
year,  there  had  been  no  improvement  at  all. 

If  in  cases  of  acromegaly  with  high-grade  brain-pressure  affections  a 
radical  operation  is  not  possible,  a  palliative  trepanation  or  an  Antonys 
"Balkenstich"  [puncture  of  the  corpus  callosum]  is  to  be  thought  of. 

The  X-ray  treatment  of  acromegaly  was  first  suggested  by  Gramegna 
and  first  practised  by  Beclere.  It  is  stated  that  retrogression  of  the  symptoms 
of  cerebral  pressure  and  improvement  in  the  visual  disturbances  have  been 
obtained  (see  also  treatment  of  hypophysial  dystrophia  adiposo-genitalis). 
A  result  can  be  expected  from  thyroid-gland  therapy  only  in  cases  complicated 
with  myxedema.  Concerning  the  treatment  of  the  more  prominent  symp- 
toms of  complicating  Basedow's,  I  refer  to  the  chapter  on  Basedow's  dis- 
ease. Otherwise  in  acromegaly  the  therapy  can  at  most  assuage  pain  by 
means  of  antineuralgics  and  eventually  combat  cardiac  insufficiency  and  the 
decay  of  strength  by  means  of  general  roborant  measures. 

b.  Hypophysial  Dystrophy 

Hypopituitarismus,  type  Frdhlich;  dystrophia  or  degeneratio  adiposo-genitalis. 

Historical. — The  occurrence  of  cerebral  adiposity  or  of  dysgenitaKsm 
in  tumors  of  the  hypophysis  was  mentioned  already  by  Bahinski,  Anderson, 
Shuster,  Uhthof,  and  others. 


HYPOPHYSIAL   DYSTROPHY  283 

In  the  year  1901,  A.  Frohlich  on  the  exhibition  of  a  case  that  came  from 
V.  Frankl-Hochwarfs  dispensary  first  coined  the  diagnostic  dictum  that 
rapidly  developing  obesity,  infantiHsm  of  the  genitalia,  and  myxedematous 
alterations  of  the  skin  suggest  tumor  of  the  hypophysis. 

The  case  reported  by  Frohlich  was  that  of  a  fourteen-year-old  boy  in  whom 
the  disease  began  two  years  before  the  presentation,  with  headaches,  vomit- 
ing, and  rapid  increase  in  weight.  He  had  a  characteristic  distribution 
of  fat,  such  as  will  be  described  later,  the  genitaha  remained  entirely  infantile, 
there  was  no  hairiness  of  the  genitalia,  the  axillary  region  and  the  trunk, 
and  the  skin  showed  shght  signs  of  myxedema.  Since  that  time  numerous 
cases  such  as  this  have  been  reported  by  v.  Frankl-Hochwarfs  assistants, 
A.  Berger,  by  Erdheim,  Zak,  A.Fuchs,  Bartels,  Madelung,  Launois  and  Cleret, 
Bahonneix  and  Peisseau,  Creuizfeld,  Neurath,  Bychowski,  Marinesco  and 
Goldstein,  Jutaka  Kon  and  others,  and  finally  several  cases  by  v.  Frankl- 
Hochwart.  A  series  of  cases  is  presented  by  the  author  in  course  of  the  follow- 
ing exposition. 

Definition. — By  hypophysial  dystrophy  we  understand  a  clinical  picture 
characterized  by  accumulations  of  fat  in  definite  places  or  eventually  by  pro- 
nounced obesity  of  definite  localization,  such  as  is  found  in  eunuchs  and  eu- 
nuchoids; further  by  inhibition  of  development  or  by  subsequent  atrophy  of  the 
interstitial  glands  and  the  glands  of  generation,  and  corres ponding  inhibition 
of  development;  or  by  more  or  less  distinct  retrogression  of  the  secondary  sexual 
characters  and  of  the  genitalia;  further,  when  the  disease  occurs  in  youthful 
years,  by  inhibition  of  growth  and  inhibition  of  ossification.  Finally,  on  account 
of  a  sluggishness  of  the  entire  metabolism,  there  is  often  added  as  a  symptom 
of  irritation  a  polyuria;  there  are  also  added  symptoms  of  pressure  on  the  part 
of  the  optic  nerves.  A  lessening  or  a  loss  of  the  function  of  the  glandular 
hypophysis  called  forth  by  processes  in  the  hypophysis  itself  or  in  the  vicinity 
of  the  hypophysis  may  be  looked  upon  as  a  cause  of  this  condition. 

Symptomatology. — One  of  the  most  important  symptoms  is  the  obesity, 
with  a  quite  definite  type  of  fat-distribution,  such  as  is  found  also  in  primary 
inhibition  of  development  of  the  genitaha.  The  agreement  in  the  distribu- 
tion of  fat  in  the  two  types  (the  primary  genital  and  the  hypophysial  dystro- 
phia adiposo-genitalis)  was  first  mentioned  by  v.  Noorden.  The  accumula- 
tion of  fat  is  chiefly  localized  to  the  hips,  the  buttocks,  the  mons  Veneris, 
and  the  mammae. 

In  the  higher  degrees  of  the  fattening  the  abdominal  wall  is  affected 
especially  in  its  lower  part,  where  there  may  develop  thick  fatty  layers. 
These  were  seen  in  several  cases;  when  they  were  removed  the  patients  felt 
considerably  reheved.  The  supraclavicular  and  infraclavicular  fossae  may 
become  quite  covered  over  by  pads  of  fat.  There  is  found,  moreover,  a  collar- 
like collection  of  fat  on  the  neck,  and  as  Launois  and  Cleret  call  them,  fatty 
cuffs  on  the  maheoK.     The  obesity  may  attain  an  excessive  grade,  but  it 


284  THE    DISEASES    OF    THE    HYPOPHYSIS 

attracts  attention  also  when  it  is  developed  only  relatively  slightly  on  ac- 
count of  its  characteristic  distribution.  Moreover,  the  hterature  frequently 
emphasizes  that  in  spite  of  the  slight  ingestion  of  food,  even  in  spite  of  the 
development  of  a  certain  cachexia,  antemortem,  the  retrogression  of  fat 
was  only  very  slight.  I  shall  later  'report  a  case  (case  Sch,  Observation 
XXXVII)  in  which  a  marked  adiposity  developed  in  a  short  time.  Then 
attacks  of  cerebral  vomiting  occurred  several  months,  on  account  of  which 
the  ingestion  of  food  was  prevented  sometimes  for  days.  The  boy  now  lost 
in  weight,  it  is  true,  but  on  account  of  the  residual  cushion  of  fat  on  the 
mons  Veneris  and  the  delicate  texture  of  the  skin  the  type  remained  still 
unmistakable. 

There  also  exist  cases  of  hypophysial  dystrophia  without  obesity.  Rennie 
reports  such  a  case  and  remarks  that  he  was  unable  to  find  a  similar  case  in 
the  literature.  Probably  in  such  cases  the  abnormal  distribution  of  fat 
would,  however,  be  recognizable.  Such  a  case  is  reported  by  Kummel.  I 
also  shall  later  report  such  a  case  (Observation  Gr,  XLV).  Moreover,  I 
shall  report  a  case  of  dystrophia  adiposo-genitalia,  probably  of  hypophysial 
origin  (Observation  Fr,  XLIV)  who  on  his  entrance  into  the  clinic  was 
very  much  emaciated  on  account  of  a  nutritional  disturbance.  In  him  also 
the  fat  collection  on  the  mons  Veneris  was  unmistakable  in  spite  of  the  ema- 
ciation. When  he  came  under  better  condition  for  nourishment  in  the  clinic, 
the  obesity  with  the  typical  fat  distribution  developed  rapidly. 

The  excessive  degree  of  obesity  is  regarded  as  endogenous.  This  con- 
ception is  based,  as  we  shall  see  later,  on  the  investigations  of  the  respiratory 
exchange  of  gases,  which  in  some  cases  of  hypophysial  dystrophy  shows  pro- 
nounced lowering  of  the  fundamental  exchange,  while  in  other  cases  the 
lowering  is  not  at  all  considerable. 

It  is  to  be  expected  that  in  hypophysial  dystrophy  just  as  in  primary 
genital  adiposity  the  muscles  are  permeated  with  fat,  as  they  are,  as  is  known, 
in  castrated  animals.  Up  to  the  present  this  condition  has  had  very  little 
attention  paid  to  it  except  that  Marinesco  andGoldstciii  report  a  case  of  typical 
dystrophy  with  microscopically  recognizable  damaging  of  the  hypophysis 
through  a  hydrocephalus,  in  which  the  fat-permeation  of  the  muscles  was 
apparently  found.  At  all  events  Marinesco  and  Goldstein  assume  a  specific 
nutritional  disturbance  of  the  muscles. 

In  dystrophia  adiposo-genitalis  the  skin  shows  a  quite  characteristic 
texture.  It  is  often  described  as  alabaster-like,  is  remarkably  delicate  and 
white,  mostly  is  cool  to  the  touch,  and  sometimes  is  dry  and  exfoliates  readily. 
In  some,  apparently  rare,  cases  myxedematous-like  swellings  of  the  skin  are 
distinctly  present.  Some  cases  are  reported  to  have  falling-out  of  the  hair 
(see  Observation  XXXIV).  On  the  contrary,  the  trophic  alterations  of 
the  nails  seem  to  be  rare. 

The  following  case  shows  typical  distribution  of  fat: 


HYPOPHYSIAL    DYSTROPHY 


^oj 


Observation  XXXIII. — J.  L.,  ten  and  one-half  years  old.     Entered  the  clinic  June, 

1909.  Has  a  poor  heredity.  Father  and  two  sisters  are  insane.  An  eight-year-old 
brother  is  hard  of  hearing.  Three  years  ago  began  violent  headaches,  that  gradually 
increased,  and  recently  there  occur,  now  and  then,  slight  attacks  of  vertigo.  Some- 
times the  lad  sees  indistinctly  and  with  blurring.  Sometimes  there  occur  parching  sen- 
sations of  thirst,  polydipsia  and  polyuria.  Obesity  has  developed  only  recently.  For  two 
years  growth  has  been  at  a  standstill. 

The  boy  is  rather  small  for  his  age. 

Height,  131  cm. 

Circumference  of  skull,  56  cm. 

Jugulm-symphysis,  4SM  cm. 

Chest  circumference,  80  cm. 

Distance  between  the  spines,  30  cm. 

Upper  extremities,  62  cm. 

Upper  arm,  24)-^  cm. 

Anterior  superior  spine  to  lower  border  of  patella,  3S  cm. 

From  there  to  internal  malleolus,  31  cm. 

The  boy  is  very  fat,  especialy  in  the  pelvic  region,  on  the  outer  side  of  the  thigh,  and 
on  the  mons  Veneris.  The  penis  is  abnormall)^  small,  the  testicles  also  small,  the  mammae 
are  very  rich  in  fat,  genua  valga. 

The  intelligence  is  normal,  the  status  of  the  nervous  system  shows  normal  conditions, 
with  the  exception  of  nystagmoid  twitching  in  all  end-positions.  Fundus  and  perimetry 
are  normal,  the  development  of  the  hand-skeleton  about  corresponds  to  the  patient's  age, 
no  alimentarj^  glycosuria  (100  gm.  dextrose). 

The  X-ray  examination  of  the  skull  shows: 

Sella  turcica  not  deepened,  but  the  entrance  to  the  sella  is  remarkabl}- broad.  This 
makes  the  clivus  somewhat  more  sharpened. 

Adrenalin  o.ooi  gm.  subcutaneously,  no  glycosuria. 

Diagnosis:  Dystrophia  adiposo-genitalis,  probably  hypophysial. 

I  cite  the  following  as  a  typical  case  of  hypophysial  dystropliia  adiposo- 
genitalis. 

Observation  XXXI]'.^ — ^L.  S.  B.  [female]  from  Russia.  Sixteen  years  old.  Entered 
the  clinic  Nov.  i,  191 1.  Family  history  shows  nothing  bearing  on  the  case.  Xine  years 
ago  the  patient  sustained  a  febrile  disorder  which  she  slates  was  typhoid  fever.  After  the 
recovery  the  body  weight  began  gradually  to  increase.  She  eats  a  fair  amount  of  food  since 
that  time,  but  especially  has  she  noticed  an  increase  of  thirst,  so  that  she  often  has  to  get  up 
at  night  to  drink.  She  also  urinates  very  frequently.  The  patient  believes  herself  to 
have  been  well  otherwise  until  about  three  years  ago.  At  that  time  she  began  gradu- 
ally to  complain  of  severe  headaches,  especially  at  night.  She  complained  of  formications  in 
the  hands,  and  remarked  that  there  was  a  decrease  in  the  power  of  vision.  Already  at  that 
time  an  eye  doctor  had  forbidden  her  to  read.  Lately  the  headaches  have  gradually 
become  worse,  especially  at  nights,  the  patient  readily  becomes  fatigued,  and  four  months 
ago  she  remarked  one  day  that  she  could  not  see  at  all  with  the  left  eye.     At  the  end  of  ]^Iay, 

1910,  an  eye  doctor  diagnosed  bitemporal  hemianopsia,  optic  nerve  atrophy,  vision  O.  D. 
10/40,  O.  S.  10  '70.  At  the  end  of  August,  1911,  there  was  a  supplementary  report,  0.  D. 
10/50,  O.  S.:  Counts  fingers  just  in  front  of  the  eye. 

At  present  there  are  headaches  almost  daily;  for  six  months  there  has  existed  falling 
out  of  the  hair,  the  nails  have  not  become  brittle;  however,  the  patient  is  almost  always 

^  The  case  has  been  also  published  in  detail  by  0.  Hirsch. 


286 


THE    DISEASES    OF    THE    HYPOPHYSIS 


listless  and  indifferent  to  all  things  that  occur  around  her,  she  yawns  very  much,  but 
sleeps  very  little  at  night.  According  to  her  statement  she  sweats  hardly  at  all.  There 
is  no  vomiting.     As  yet  she  has  not  menstruated. 

The  patient  is  small,  about  145  cm.  The  build  of  the  bones  is  slender,  the  musculature 
poorly  developed,  the  layer  of  fat  very  abundant.  Especially  fat  are  the  mammae,  in 
which  no  trace  of  glandular  substance  is  palpable.  The  nipples  are  small  and  retracted. 
Especial  accumulations  of  fat  are  found  on  the  hips,  on  the  outer  sides  of  the  thighs,  and  on 
the  nions  Veneris.  The  axillce  as  well  as  the  mons  Veneris  possess  only  a  very  few  hairs. 
The  genitalia  arc  rudimentary.  The  labia  minora  are  scarcely  developed.  The  clitoris 
is  very  short,  hymen  intact.     The  uterus  very  small,  the  ovaries  are  not  felt. 


Fig.  51. — Case  of  dystrophia  adiposo-genitalis.        Fic.  52. — Hypophysial  dystrophy. 

The  patient  shows  great  difficulty  in  thinking.  She  speaks  German  well  enough  it  is 
true,  but  responds  to  only  very  simple  questions.  In  Russian  she  converses  rather  fluently. 
She  lies  in  bed  very  much,  and  is  indijfcrent  to  her  surroundings.  During  the  examination 
she  yawned  very  much. 

The  left  eye  is  amaurotic,  the  pupils  do  not  react  although  the  consensual  reaction  is 
present.  On  the  right  side  is  temporal  hemianopsia  and  temporal  Jtemianopic  pupillary 
reaction.  Vision  of  0.  D.  i/io.  Both  papillae  are  sharply  demarcated  and  atrophic.  The 
reflexes  are  normal.  The  neck  is  short,  thick,  the  thyroid  not  palpable.  The  supra- 
clavicular and  infraclavicular  fosscB  as  well  as  the  intercostal  spaces  are  entirely  obliterated 
by  the  pads  of  fat.     The  abdominal  walls  are  extremely  fal.     The  fatty  tissue  of  the  skin 


HYPOPHYSIAL    DYSTROPHY  287 

is  everywhere  markedly  sensitive  to  pressure.     The  amount  of  urine  is  4000  cc,  specilic 
gravitv,  1008. 


Fig.  53. — Widened  and  deepened  sella  in  h\-poph\-sial  d\-stroph3'  (Observation  XXXIV). 

Hemoglobin,  according  to  SaJili,  75  per  cent. 
Leucocytes,  S400  of  which: 


8  THE    DISEASES    OF    THE    HYPOPHYSIS 

Xeutrophiles,  56.1  per  cent. 

Lymphocytes,  35.8  per  cent. 

Eosinophiles,  3.2  per  cent. 

Large  mononuclears,  4.9  per  cent. 

Body  weight,  62  kg. 

Temperature  varies  between  36"  and  36.6° 

Alimentary  glycosuria  (200  gm.  dextrose)  negative 

The  blood  sugar  is  0.0826  per  cent.  {Dr.  Bernstein) 


Fig.  54. — X-riiy  picture  in  Observation  XXXIV. 

X-ray. — Cranial  vault  of  normal  size  and  form.  Internal  surface  smooth,  sutures  are 
present,  sella  moderately  widened  and  deepened.  Its  floor  shows  an  anterior  arching 
forward  and  a  thinning.  The  dorsum  sellae  is  thinned,  the  anterior  clinoid  processes  are 
retained.  Sphenoidal  sinuses  capacious.  The  ossification  of  the  hand  skeleton  about 
fits  in  with  the  age. 


HYPOPHYSIAL   DYSTROPHY  289 

The  patient  was  operated  on  Nov.  29,  191 1,  by  Dr.  O.  Hirsch  at  the  Urbantschitsch 
clinic,  under  local  anesthesia.  The  septum  was  subjected  to  a  submucous  resection, 
both  sphenoidal  sinuses  were  opened,  the  floor  of  the  sella  was  chiseled  off,  and  the  tumor 
partially  curetted  out,  and  partially  removed  through  suction  through  a  glass  tube.  The 
total  mass  together  with  the  blood,  measured  about  45-50  cc.  There  was  no  fever  for  the 
first  two  days  after  the  operation,  then  on  the  third  day  the  temperature  suddenly  rose 
to  39.5°.  Vomiting  that  lasted  for  five  days.  There  was  probably  a  hematoma  in  the 
dural  sac  of  the  hypophysis,  that  went  over  into  suppuration,  was  in  part  absorbed, 
and  in  part  flowed  off  (Hirsch);  for  several  days  the  fever  was  very  high,  39-40.5°.  The 
third  and  fourth  weeks  it  gradually  declined.  At  the  end  of  the  fourth  week  the  patient 
was  retransferred  to  the  first  medical  clinic.  The  patient  now  makes  an  entirely  different 
impression,  she  is  incomparably  more  lively,  is  interested  in  the  surroundings  and  promptly 
answers  all  questions.  The  falling  out  of  hair  has  lessened.  The  thirst  still  exists.  She 
yawns  much  less,  the  hairiness  of  the  axillae  and  of  the  mons  Veneris  has  increased,  the 
visual  power  of  0.  D.  has  risen  from  i/io  to  i. 67/10.  ■  The  headache  disappeared  entirely 
after  the  operation,  but  reappeared  again  four  weeks  afterward.  Very  noteworthy  are  the 
blood-findings.     The  differential  count  now  shows: 

Neutrophiles   71  per  cent. 

Lymphocytes,  25  per  cent. 

Eosinophiles,  i  per  cent. 

Mononuclears,  2  per  cent. 

Transitional  forms,  i  per  cent. 

There  is  now  distinct  reduction  on  the  ingestion  of  100  gni.  of  dextrose. 

The  patient  has  lost  about  6  kg. 

In  typical  dystrophia  adiposo-genitalis  is  found,  in  addition  to  the 
fattening,  an  inhihition  of  the  development  of  the  genitalia  and  of  the  secondary 
sexual  characters;  in  male  individuals  the  penis  remains  quite  small  and 
may  even  be  entirely  buried  in  the  fat  cushions  (see  Observation  Sch, 
XXXVII),  the  scrotum  also  remains  small,  the  testicles  remain  quite 
diminutive  and  are  usually  entirely  undescended  or  partially  descended  on 
one  or  on  both  sides.  Also  the  prostate  remains  abnormally  small.  In 
female  individuals  the  external  and  internal  genitalia  remain  quite  infantile; 
the  labia  minora  are  developed  but  very  poorly,  the  clitoris  is  short,  the  uterus 
infantile,  the  ovaries  may  be  not  palpable,  the  breasts  as  a  rule  are  indeed 
very  rich  in  fat,  but  are  poor  in  glandular  substances  (see  Observation 
XXXIV).  The  nipples  are  small  and  retracted.  Moreover  there  is  either 
no  hairiness  of  the  axillae,  the  pubic  region,  and  the  perineum,  or  in  the  pubic 
region  there  are  only  a  few  bristly  hairs.  Men  remain  beardless.  The  voice 
does  not  change  or  changes  very  incompletely.  The  vita  sexualis  does  not 
develop,  and  menstruation  and  ovulation  do  not  occur.  In  certain  cases  in 
which  the  disease  has  developed  after  puberty,  there  have  been  reports  as 
to  subsequent  falHng  out  of  the  beard  hair  and  the  pubic  hair,  in  men  im- 
potence sets  in,  and  there  is  a  cessation  of  erection  and  ejaculation;  in 
women  there  is  a  cessation  of  menstruation.  Libido  disappears  in  both  the 
sexes.  There  may  also  occur  a  partial  retrogression  of  an  accessory  genital 
apparatus  that  once  was  fully  developed  (see  Observation  G,  XLV). 
19 


290  THE    DISEASES    OF    THE    HYPOPHYSIS 

The  Metabolism. — Very  few  investigations  as  to  the  metabolism  of 
hypophysial  insufficiency  have  as  yet  been  made.  Already  clinical  observa- 
tions would  indicate  that  in  hypophysial  dystrophy  there  are  considerable 
alterations  in  metabohsm.  We  not  rarely  find  the  statement  that  on  the 
one  hand,  at  the  beginning  of  the  disease  there  occur  a  transitory  polyphagia 
and  increased  appetite.  I  refer  to  S,  Observation  XXXIV  and  Sch,  Observa- 
tion XXX\'II.  to  be  reported  later.  On  the  other  hand,  obesity  that  develops 
gradually  and  which  in  certain  cases  may  attain  an  excessive  degree  suggests 
a  reduction  in  the  metabolism. 

Also  the  observation  that  after  operation  there  is  often  an  appreciable 
reduction  of  body  weight  speaks  to  the  same  effect.  Statements  as  to  this 
question  are  made  by  v.  Frankl-Hochwart,  concerning  the  first  case  that 
V.  Eiselsherg  operated  on  with  good  results.  Also  in  the  case  of  Hirsch, 
previously  mentioned  (Observation  S,  XXXIV),  a  reduction  of  6  kg.  in 
weight  followed  during  a  short  time  after  the  operation. 

The  investigations  as  to  the  fundamental  exchange  or  the  rest  exchange 
in  dogs  in  which  the  hypophysis  had  been  removed  show  unequivocally 
an  appreciable  reduction  of  the  respiratory  gaseous  exchange  {Benedict  and 
Romans,  Forges  and  Aschner). 

The  first  experiments,  in  two  cases  of  hypophysial  dystrophy  as  reported 
in  the  second  edition  of  v.  Noorden's  book  on  ''Obesity."  These  experiments 
which  were  carried  out  by  Forges  gave  rather  normal  values.  The  cases  were 
undoubted  cases  of  hypophysial  dystrophy  and  had  been  described  by  v. 
Frankl-Hochwart.  Later  Bernstein  found  an  appreciable  reduction  in  one 
case.  Finally  Bernstein  and  /  have  recently  investigated  a  case.  I  here 
tabulate  the  cases  thus  far  investigated. 


Investigator 

Case 

Age 

Height 

Weight 

CO2 

0. 

Porges,  cited  by  v.  Noorden. . 

Bernstein 

Bernstein  and  Falta 

G.  \\i 
Fr. 

25 

28 

15 

166 
149 
121 

70 
65-62 

33       : 

1 

3-35 
2.94 
6. II 

2. 29 

5-14 

(25,  formerl}') 


The  few  cases  do  not  furnish  any  certain  conclusion.  Only  in  Bern- 
stein's case  is  the  respiratory  metabolism  certainly  reduced.  This  obser- 
vation hence  coincides  with  the  experiences  met  with  in  animal  experimenta- 
tion. In  case  Fr,  Observation  XXXIV,  values  of  comparison  with  values 
furnished  by  a  normal  individual  equally  heavy  and  tall  are  lacking. 

The  observation  as  to  the  carbohydrate  metabolism  in  hypophysial  dys- 
trophy show  a  noteworthy  opposite  behavior  to  that  in  acromegaly.  While 
in  acromegaly,  in  the  great  majority  of  cases,  we  find  the  tolerance  for  carbo- 
hydrates more  or  less  reduced,  this  has  not  as  yet  been  found  in  hypophysial 
dystrophy.     On  the  contrary  it  seems,  so  far  as  investigations  up  to  the 


HYPOPHYSIAL    DYSTROPHY  29I 

present  have  shown,  that  the  hmits  of  assimilation  are  raised  {Bondi,  cited 
by  V.  Frankl-Eochwart;  v.  Noorden,  and  others).  I  here  pubhsh  all  of  my  own 
observations  of  dystrophy,  equally  whether  the  diagnosis  hypophysial  dis- 
turbance has  made  certain,  or  whether  it  is  merely  tentative. 

Observation  L,  XXXIII,  alimentary  glycosuria  (100  gm.)  negative. 

Observation  Si,  XXXIV,  alimentary  glycosuria  (200  gm.)  negative. 

Observation  Si,  XXXIV,  after  operation,  alimentary  glycosuria  (100  gm.)  distinct  re- 
duction. 

Observation  Sch,  XXXVII,  alimentary  glycosuria  (100  gm.  D)  negative. 

Observation  K,  XXXVIII,  alimentary  glycosuria  (100  gm.  D)  negative. 

Observation  W,  XXXIX,  alimentary  glycosuria  (100  gm.  D)  negative. 

Observation  P,  XLIII,  alimentary  glycosuria  (200  gm.  D)  negative. 

Observation  F,  XLIV ,  alimentary  glycosuria  (200  gm.  D)  negative. 

Observation  G,  XLV,  alimentary  glycosuria  (200  gm.  D)  negative. 

Observation  G,  Wi.,  XXXVI,  alimentary  glycosuria  (100  gm.  D)  negative,  alimentary 
glycosuria  (200  gm.  D)  trace. 

Observation  E.  M.,  XXXV  (200  gm.  D)  negative. 

From  the  observation  on  pertinent  cases  in  the  literature  as  well  as  the 
cases  here  reported  is  elicited  the  fact  that  in  hypophysial  dystrophy  there  is 
no  inclination  to  glycosuria,  but  on  the  contrary  an  abnormal  high  tolerance  for 
carbohydrates.  A  single  exception  exists  in  the  case  of  Link,  a  case  of  hypophy- 
sial tumor  without  acromegaly  and  with  diabetes.  We  shall  simply  state  this 
fact  here  and  return  to  it  in  the  discussion  of  the  theory. 

Investigations  as  to  the  contents  of  sugar  in  the  blood  are  up  to  the 
present  scarce.  Gushing  states  that  in  certain  cases  he  found  an  abnormally 
low  amount  of  sugar  in  the  blood.  Bernstein  estimated  the  sugar  in  the  blood 
in  two  of  the  cases  here  reported.  Both  were  certain  cases,  in  one  of  which 
(Observation  S,  XXXIV)  the  diagnosis  was  verified  on  operation,  in  the  other 
(Observation  G,  XLV)  at  autopsy.  The  values  were  0.082  per  cent,  in  case 
S,  0.081  per  cent,  in  case  Gr,  therefore  normal. 

Investigations  as  to  purin  metabolism  have  as  yet  been  carried  out  only 
by  Nowacznski  and  myself. 

In  the  one  case  the  following  was  noted: 

Observation  A'.YA'F. — E.  M.,  forty-four  years  old.  Entered  clinic  March  29,  1912. 
Six  years  ago  sustained  a  sprain  of  the  lumbar  spine  by  a  blow  from  a  stay.  Present 
disease  began  about  six  weeks  ago  with  vomiting.  Severe  headache,  twelve  days  ago 
diplopia.  Flickering  before  the  eyes,  weakness  of  vision.  Patient  is  a  heavy  drinker; 
no  venereal  diseases;  for  several  months  increase  of  weight,  reduction  of  libido  and 
potency. 

Vigorous  man,  sensorium  unimpaired,  distinct  abducens  palsy  of  left  eye.  Left 
palpebral  fissure  narrower  than  right.  Left  pupil  wider  than  right.  Pupillary  reaction  on 
right  prompt,  on  the  left  delayed.  Diplopia  on  looking  toward  the  left.  Nystagmus  of 
left  eye  on  looking  toward  left.  Facialis  normal.  Tremor  of  the  hands,  otherwise  no 
motor  or  sensory  disturbance. 

No  ataxia.  Reflexes  normal.  X-ray:  Sella  turcica  itself  is  normal,  but  the  clivus  is 
atrophic  as  corresponds  to  the  generally  increased  cerebral  pressure. 


292  THE    DISEASES    OF    THE    HYPOPHYSIS 

Alimentary  glycosuria  (200  gm.)  negative. 

Diagnosis:  Dystrophia  adiposo-genitalis  due  to  tumor  in  the  region  of  the  hypophj'sis. 

The  investigation  of  elimination  of  uric  acid  on  a  purin-free  diet  gave  the  following 
values: 

o. 398-0. 4o6-(20  gm.  sodium  nucleinate  by  mouth)  0.434-0.593.  The  endogenous 
uric  acid  value  hence  lies  rather  low.  at  all  events  the  elimination  of  uric  acid  after  the 
administration  of  purin  is  very  low. 

The  second  case  was  the  following: 

Observation  XXXVI. — G.  Wi.,  twenty-eight  years  old  [female].  Entered  the  clinic 
May  I,  191 2.  For  one  year  headache  without  definite  localization.  Vertigo,  vomiting, 
ear  noises  at  intervals  of  months,  which  for  the  last  three  months  have  occurred  almost 
weekly.  Since  childhood,  slight  weakness  of  vision  on  the  left.  For  the  last  six  months, 
decrease  of  vision  on  both  sides,  amaurosis  on  the  left,  still  some  vision  remains  on  the 
right,  for  the  last  months  increase  of  weight.  Absent  menstruation  for  the  last  nine 
months.     Lues  denied. 

Findings  as  concerning  the  lungs,  heart,  etc.,  normal;  rather  fat,  especially  on  the 
abdomen.  Pupils  unequal,  left  larger  than  the  right.  The  left  has  lost  its  round  contour, 
does  not  react  to  light,  the  right  reacts  slowly.  Accommodation  on  both  sides  good,  globe 
free,  no  nystagmus,  corneal  and  conjunctival  reflexes  present.  Fundus  normal,  right 
temporal  hemianopsia,  basal  limitation  of  the  visual  field,  left  amaurosis;  facial  nerve  nor- 
mal. Face  hyperalgetic;  trigeminus  sensibility,  temperature-sense,  pain-sense,  motility 
and  motor  power  normal.  Patellar  reflexes  lively.  Suspicious  Babinski  reflex  on  the  left. 
Abdominal  reflexes  present.     No  vertigo,  no  diplopia. 

X-ray:  Sella  turcica  dilated  quite  lightly,  especially  in  the  infundibular  part.  This 
finding  does  not  speak  unconditionally  for  hypophysial  tumor,  but  may  be  present  in  other 
brain  tumors. 

Alimentary  glycosuria:  (100  gm.  D)  negative;  (200  gm.  D)  trace. 
The  investigations  of  the  uric-acid  elimination  on  a  purin-free  diet  show  the  following 
values: 

o.287-o.334-(2o  gm.  sodium  nucleinate  by  mouth)  0.513-0.206-0.298-0.214. 
Hence  the  endogenous  factor  lies  even  lower  than  in  the  preceding  case.     Administra- 
tion of  purin  increases  the  elimination  of  uric  acid  but  very  little. 

Quantities  of  urine  up  to  2400  cc.  with  specific  gravities  between  1005  and  loio. 
Investigations  as  to  the  gaseous  exchange  {Bernstein) — average  of  seven  investigations. 
CO2  elimination,  2.29 
Oo  consumption  2.94 
Blood-count:  Erythrocytes,  4,600  000 
Hemoglobin,  84  per  cent. 
Leucocytes,  7800  of  which: 
Polymorphonuclear  leucocytes,  74.1  per  cent. 
Lymphocytes,  19.5  per  cent. 
Eosinophiles,  0.7  per  cent. 
Large  mononuclears,  5.7  per  cent. 
At  the  beginning  of  the  stay  at  the  clinic  the  patient  was  very  sleepy,  and  uninterested. 
Later  there  developed  a  clinical  picture  similar  to  Korsakoff's  psychosis,  and  the  patient 
was  transferred  to  i'.  Wagner^s  clinic.     Increasing  weakness,  lately  Babinksi  reflex  positive 
on  each  side.     Facial  palsy  on  the  left  and  pareses  of  the  lower  extremities.     Pneumonia. 
Death. 

August  6,  191 2.  Necropsy  (assistant  Erdhcim)  showed:  Cystic  hypophysial  tumor 
of  the  size  of  an  apple,  at  the  base  of  the  brain,  at  the  site  of  the  infundibulum,  with  pro- 


HYPOPHYSIAL    DYSTROPHY  293 

trusion  of  the  tumor  into  the  third  ventricle  and  giving  off  of  the  peduncle  of  the  hj^po- 
physis  from  its  lower  surface.  The  tumor  extends  to  the  circle  of  Willis  and  hollows  out  • 
considerably  both  the  temporal  lobes;  at  the  anterior  pole  of  the  tumor  lie  the  flattened 
optic  nerves,  which  are  wedged  in  between  the  tumor  and  the  anterior  cerebral  arteries 
and  which  show  a  squeezing  together  at  this  place;  more  on  the  left  than  on  the  right;  the 
lower  pole  of  the  tumor  lies  at  the  entrance  to  the  sella  turcica  and  dilates  it.  The  dorsum 
sellse  is  moderately  eroded,  the  floor  of  the  sella  distinctly  eroded,  but  moderately  deep- 
ened. In  the  sella  is  the  hypophysis,  which  is  of  normal  size  with  a  slight  concavity  of  its 
upper  surface.  The  tumor  is  a  unilocular  thin-walled  cyst,  in  the  clear  j-ellowish  contents 
of  which  float  consistent  opaque  flakes.     General  adiposity. 

A  third  case,  which  since  this  time  has  been  investigated  by  Dr.  Vias  and 
myself,  is  later  set  forth  in  detail.  (Observation  F,  XLIV).  It  was  that 
of  a  juvenile  dystrophy,  the  hypophysial  origin  of  which  is  only  conjectural. 

Therefore,  in  all  three  cases  the  endogenous  uric-acid  value  is  at  the 
lower  Kmit  of  the  normal,  and  the  elimination  of  any  purin  that  is  adminis- 
tered is  protracted.  Of  course  there  exists  the  possibility  that  in  such  cases 
the  absorption  of  sodium  nucleinate  is  incomplete.  After  all,  even  in  this 
respect,  there  is  a  noticeable  difference  from  the  state  of  affairs  in  the  cases 
of  acromegaly  investigated. 

Investigations  as  to  the  behavior  of  the  vegetative  nervous  system  in 
hypophysial  dystrophy  are  up  to  the  present  very  scarce.  As  far  as  the  ex- 
citabihty  of  the  vegetative  nerves  through  pharmacological  means  is  con- 
cerned, I  can  mention  only  the  following:  the  glycosuric  action  of  adrenalin 
(i  mg.)  has  failed  in  the  cases  I  have  thus  far  examined  (Observations 
XXXIII  and  XLIII,  see  later). 

After  the  injection  of  o.oi  gm.  of  pilocarpine  in  case  Si  (XXXIV),  there 
was  only  a  A^ery  slight  sweat.  After  the  injection  of  pituitrinum  infundibu- 
lare  (2-3  cc.  Parke,  Davis  &"  Co.'s  preparation)  there  could  be  obtained  a 
marked  diuretic  action.  Hence  the  excitability  of  the  vegetative  nerves 
seems  to  be,  as  in  myxedema,  generally  reduced.  Perhaps  the  nervous 
mechanism  regulating  temperature  forms  an  exception  to  this  (see  part  deal- 
ing with  the  temperature). 

Many  circumstances  speak  for  the  fact  that  there  is  a  reduction  in  the 
tonus  of  certain  vegetative  nerves.  In  all  cases  we  find,  for  exapiple,  state- 
ments as  to  the  dryness  of  the  skin  and  the  lessened  tendency  to  sweats. 

Here  I  might  mention  the  statements  of  v.  Frankl-Hochwart,  and  Frohlich, 
that  in  hypophysial  dystrophy  there  not  infrequently  occur  vesical  disturb- 
ances. For  the  most  part  they  have  been  referred  to  the  compression  of  the 
pes  pedunculi  by  the  growing  h}-pophysial  tumor;  both  authors  express  the 
opinion  that  perhaps  a  reduction  of  the  function  of  the  posterior  lobe  and 
lack  of  pituitrinum  infundibulare  is  responsible.  It  would  indeed  be  impor- 
tant to  pay  attention  to  the  behavior  of  the  vesical  disturbances  in  those 
cases  in  which  transitory  polyuria  points  to  an  irritation  of  the  posterior 
lobe.     I  shall  consider  this  symptom  somewhat  in  detail. 


294 


THE    DISEASES    OF    THE    HYPOPHYSIS 


We  find  that  polyuria  or  polydipsia  has  been  mentioned  in  the  history 
rather  frequently.  In  v.  Frankl-Hochwart's  statistics  the  picture  of  diabetes 
insipidus  occurred  seven  times.  When  I  turn  to  the  newer  hterature  I  find 
that  polyuria  or  at  least  transitory  attacks  of  thirst  are  very  frequent.  I 
cite  the  following  case: 

Case  I  of  Zack. — Transitory  polyuria,  with  urine  of  looo  specific  gravity. 
Case  Fuchs.. — At  times  attacks  of  thirst. 

Case  Rosenhaupt. — An  average  of  ^^'2  liters  of  urine.  Autopsy  showed  a 
sarcoma  of  the  anterior  lobe  of  the  pituitary. 

Case  I  of  Bartels. — Twenty-one-year-old  man. 
Polydipsia  very  pronounced. 

Case  I  of  Cagnetto. — Nine-year-old  girl,  poly- 
dipsia. 

Case  Gotzl-Erdheim. — Diabetes  insipidus. 
Own  Observation  (L,  XXXIII). — Sometimes 
intense  feeling  of  thirst  and  polyuria. 

Own  Observation  (Si,  XXXIV). — Polydipsia 
and  polyuria,  must  get  up  several  times  at  night. 
Own  Observation   (Wi,   XXXVT). — At    times 
polyuria,  with  urine  of  low  specific  gravity. 

Own  Observation  (F,  XLIV). — Amounts  of 
urine  up  to  4000,  specific  gravity  1005-1010. 

Also  a  case  of  Frank's  perhaps  belongs  here: 
a  thirty-nine-year-old  corpulent  man  several  years 
ago  attempted  suicide  by  firing  two  bullets  into 
the  right  temple.  Six  to  seven  liters  of  urine 
daily,  of  specific  gravity  1005.  Libido  lost;  X-ray 
shows  one  of  the  bullets  in  the  median  line,  pro- 
jecting into  the  sella  turcica  from  above. 

Hence  there  are  found  in  a  great  number  of 
cases  of  hypophysial  dystrophy,  transitory  or  more 
permanent  polyuria,  indeed  in  many  cases 
the  condition  may  assume  the  ])icture  of  a  severe 
diabetes  insij^idus. 

The  combination  with  polyuria  occurs  not 
only  in  diseases  of  the  hypophysis  but  also  in  dis- 
eases that  affect  the  neighborhood  of  the  hypophysis  (vicinity  of  the  chiasma, 
subthalmic  region,  etc.).  As  we  shall  consider  these  cases  later  in  the  dis- 
cussion of  the  pathogenesis  I  shall  bring  to  the  front  the  most  essential  facts 
in  the  existing  chnical  material.  Oppcnheim  first  ])ointed  out  that  polyuria 
frequently  occurs  in  gummatous  diseases  of  the  chiasm.  Of  thirty-six 
cases  of  basal  luetic  meningitis  from  the  literature,  twelve  had  polyuria. 
Oppenheim  himself  reports  two  cases  with  autopsies.     Spanbeck  and  Stein- 


FiG.  55- — Tumor  of  the 
subthalmic  region  with 
diabetes  insipidus. 


HYPOPHYSIAL   DYSTROPHY  295 

haus  found  diabetes  insipidus  eleven  times  among  fifty  cases  with  bitemporal 
hemianopsia.  They  themselves  report  a  case  of  typical  hemianopsia,  which 
eliminated  6-7  hters  of  urine  with  a  specific  gravity  of  1002.  Mercury  and 
iodine  treatment  brought  about  complete  cure. 

I  here  report  a  case  I  saw  a  long  time  ago  that  in  many  respects  is  very 
interesting. 

Observation  XXXVII. — A.  Sch.,  fifteen  years  old.  Entered  the  clinic  Sept.,  1909. 
Father  and  mother  well;  no  nervous  affection  in  the  family.  The  mother  had  had  four 
deliveries  and  three  abortions.  The  first  child  is  entirely  well,  the  second  is  the  patient. 
The  third  and  fourth  children  had  had  transitory  illnesses  that  were  without  relevance 
to  the  patient's  condition. 

The  patient  has  had  a  remarkably  large  head  ever  since  birth.  The  first  tooth  ap- 
peared in  the  sixth  month,  and  he  began  to  walk  at  the  age  of  two  years.  At  this  time  he 
was  remarkably  tall — a  giant  child.  At  three  years  of  age  there  developed  gradually 
convergent  strabismus  that  has  existed  up  to  the  present  time.  The  boy  learned  well  at 
school,  and  was  even  very  intelligent  and  lively.  From  the  age  of  twelve  years  there 
developed  a  gradual  lessening  of  visual  power;  vertigo  often  occurred,  the  boy  had  very  great 
thirst,  had  to  drink  very  much  and  urinated  very  much.  Also  the  statement  is  made  by  the 
mother  that  at  this  time  the  boy  had  a  remarkably  large  appetite.  He  also  had  to  expecto- 
rate very  much.     Gradual  increase  of  body  weight  became  apparent. 

In  1908  the  patient  had  been  at  v.  Neusser's  clinic.  There  it  was  noted  that  there  was 
marked  panniculus  adiposis.  Body  weight  46.8  kg.  Slight  concomitant  convergent 
strabismus.  The  movements  of  the  eye-balls  toward  all  directions  are  very  good,  how- 
ever. ■  The  penis  is  small,  no  pubic  hair,  patellar  reflexes  lively,  temporal  paleness  of  both 
papillce.  Field  of  vision  normal.  Amounts  of  urine  between  2500  and  4500.  Specific 
gravity  about  1008. 

According  to  mother's  statement  the  emaciation  began  during  the  mentioned  stay  at 
the  clinic.  Since  that  stay  there  have  also  existed  severe  headaches  that  occur  about  twice 
weekly  and  are  especially  localized  in  the  frontal  region.  During  severe  attacks  there 
exist  marked  sensation  of  heat  and  reddening  of  the  skin  of  the  face  with  outbreak  of  sweat, 
vertigo  and  flickering  before  the  eyes  and  mostly  severe  vomiting.  Between  these  attacks 
there  exists  great  tendency  to  sleep,  the  boy  sleeping  twelve  hours  uninterruptedly. 
According  to  the  mother,  there  is  a  common  inclination  for  yawning.  The  boy  states 
that  now  and  then  erections  occur.  The  polyuria  is  now  very  considerable.  It  now  is 
as  much  as  seventy-one  times  daily,  and  he  must  get  up  often  at  nights  to  urinate. 
According  to  the  definite  statement  of  the  mother,  the  boy  has  not  grown  for  a  year. 

The  boy  is  tall,  the  body  shows  the  following  measurements: 

Jugulum  to  ant.  sup.  spine,  38.5  cm. 
Jugulum  to  symphysis,  46  cm. 
Vertebra  prominens  to  coccyx,  47  cm. 
Circumference  of  chest,  72  cm. 
Circumference  of  pelvis,  71  cm. 
Upper  extremities,  68  cm. 
Lower  extremities,  72  cm. 

The  face  has  a  more  childish  expression  than  corresponds  to  the  age.  The  intelligence 
is  entirely  normal,  rather  more  mature  than  corresponds  to  the  age.  Hair  is  absent  in  the 
axilte  and  on  the  pubes,  also  on  the  perineum.  The  boy  is  extremely  emaciated,  especially 
on  the  extremities;  the  most  fat  is  found  on  the  outer  surface  of  the  thighs.     The  mons  Veneris 


296 


THE    DISEASES    OF    THE   HYPOPHYSIS 


is  verv  rich  in  fat.     The  penis  is  smalL  and  on  both  sides  the  very  small  testicles  rcniai)i  in  the 
inguinal  canal. 

The  strabismus  remains  unaltered.  The  examination  of  the  fundus  shows  on  both  sides 
temporal  paling  of  the  papilla'.     Perimeter  normal. 

X-ray  examination  that  had  been  made  even  before,  the  patient's  entrance  into  the 
clinic  shows  entirely  normal  relations  of  the  sella  turcica.  Examination  of  the  hand-skeleton 
shows  that  the  epiphysial  junctures  and  the  rudiments  of  the  hand-skeleton  correspond 
fully  to  the  age.  The  patellar  reflexes  are  lively,  but  with  the  exception  of  the  nervous 
status  there  is  nothing  else  especial. 

Alimentary  glycosuria  (100  gm.  D)  negative. 

The  amounts  of  urine  vary  between  4000  cm.  and  6700  cm.  The  specific  gravity  is 
1002-1003. 

During  the  stay  at  the  clinic  an  attack  of  headache  and  vomiting  occurred  such  as 
is  already  described.  This  lasted  for  tw-o  and  one-half  days,  the  vomiting  was  uncontrol- 
lable.    Ingestion  of  food  during  this  time  nil.     Ingestion  of  fluid  very  slight,  only  1600 

cm.,  or  500  cm.,  or  1050  cm.  The  specific 
gravity  {of  the  urine)  rose  to  1013.  The  boy 
during  this  time  lost  3  kg.,  falling  from  37}^ 
kg.  to  343.2  kg. 

The  patient  died  a  half-year  after  his  en- 
trance into  the  clinic. 

Summary. — When  the  patient  came  into 
the  clinic,  he  showed  the  entire  picture  of  dys- 
trophia adiposo-genitalis.  As  X-ray  exami- 
nation shows  the  sella  turcica  to  be  normal, 
it  may  well  be  assumed  that  a  tumor  pressed 
on  the  hypophysial  peduncle  from  above. 
Also  the  diabetes  insipidus  fits  into  the  pic- 
ture, also  the  undoubted  temporal  paling  of 
the  papillae,  which  had  not  as  yet  led  to  a 
demonstrable  hemianopsia.  It  is  further 
noteworthy  that  the  concentrating  power  of 
the  kidneys  was  still  present  under  certain 
circumstances. 


Fig.  56. — Genitalia  of  Observation 
XXXVII. 


Very  noticeable  is  also  the  statement  of  Slrauss  as  to  cases  of  diabetes 
insipidus  combined  with  corpulency  of  the  hypophysial  type,  with  lack  of 
pubic  and  axillary  hair  and  with  hypoplasia  of  the  genitals.  In  many 
such  cases  we  are  perhaps  deahng  with  developing  tumors  of  the  vicinity 
of  the  hypophysis,  even  though  there  are  as  yet  no  other  signs  of  brain 
tumor. 

As  an  example  of  this  type,  I  cite  the  following  case: 

Observation  A' A' AT///. — S.  K.,  twenty-one  years  old.  Entered  the  clinic  July  12, 
191 2.  Mother  of  the  patient  was  corpulent,  and  died  of  brain  tumor.  The  patient's 
corpulency  began  in  the  thirteenth  year  of  life,  together  with  increased  sensation  of  thirst, 
the  patient  sometimes  drinking  5  liters  of  water  a  day.  Corresponding  polyuria.  This 
has  continued  since  that  time,  and  only  during  the  last  three  years  has  it  become  somewhat 
slighter.  For  years  violent  headaches,  which  of  late  have  been  increasing  in  intensity  and 
frequency.     The  patient  has  not  as  yd  had  sexual  intercourse,  although  according  to  his 


HYPOPHYSIAL    DYSTROPHY  297 

statement  there  exists  a  certain  amount  of  libido  and  vita  sexualis,  and  he  believes  that 
he  would  have  potentia  coeundi.  He  states,  however,  that  nightly  pollutions  almost  never 
occur. 

About  170  cm.  tall,  the  skin  quite  soft,  mustache  and  beard  are  almost  completely  ab- 
sent, axillae  show  but  very  sparse  hairiness,  on  the  mons  Veneris  rather  good,  closing  off 
above  in  a  horizontal  line,  otherwise  hairiness  of  the  trunk  and  extremities  is  entirely 
absent. 

Typical  eunuchoid  fat  deposits.     Mammae  extremely  rich  in  fat,  as  are  also  the  vicin- 
ity of  the  hip,  and  the  mons  Veneris.     The  small  penis  is  embedded  in  a  cushion  of  fat. 
Testicles  of  rather  normal  size  and  consistency.     Genu  valgum  on  each  side. 
Alimentary  glycosuria  (100  gm.  dextrose),  negative. 
Blood  count:  Erythrocytes,  4,240,000 
Hemoglobin  (Sahli),  65  per  cent. 
Leucocytes,  6500,  of  which: 
Neutrophiles,  65  per  cent. 
Mononuclears,  28  per  cent. 
Eosinophiles,  7  per  cent. 
X-ray  examination  of  the  skull  shows  normal  relations. 

On  freely  chosen  administration  of  liquid,  an  average  of  7400  cc.  of  urine  per  day. 
The  investigation  as  to  the  specific  gravity  of  the  urine  at  different  times  of  the  day  shows 

1008 
1008 
1004 
1002 


6-1 1 

A.M. 

1550 

cc. 

1 1-4 

P.M. 

1300 

cc. 

4-9 

P.M. 

1900 

cc. 

9-6 

A.M. 

1600 

cc. 

After 

addition 

of 

15  gm. 

of 

common 

salt  to  the 

breakfast 

6-1 1 

A.M. 

1200 

cc. 

1 1-4 

P.M. 

1850 

cc. 

4-9 

P.M. 

1950 

cc. 

9-6 

A.M. 

2600 

cc. 

1007 
1007 
1007 

1004 

Summary. — Combination   of   eunuchoid   obesity  and  deficient  development  of  the 

secondary  sexual  characters  with  diabetes  insipidus.  Growth-disturbance  is  absent,  as  is 

also  any  disturbance  worth  while  in  the  ossification.  Probably  disease  of  the  brain-stem 
of  unknown  nature. 

V.  Frankl-Hochwart  emphasizes  that  in  tumors  of  the  hypophysis  without 
acromegaly,  often  the  temperature  is  estabhshed  at  subnormal  values;  he 
himself  observed  this  in  three  of  ten  cases.  In  the  case  of  Gotzl-Erdheim  the 
temperature  varied  between  35°  and  36°,  only  exceptionally  rising  as  high 
as  36.3°.  Among  my  cases  this  was  very  evident  in  case  Si,  Observation 
XXXIV,  here  the  temperature  varied  for  a  time  between  36°  and  36.6°; 
and  in  case  F,  Observation  XLIV  (see  later),  the  temperature  varied  for  a 
while  between  36°  and  36.4°;  and  later  even  between  35.8°  and  36.2°.  We 
could  bring  this  reduction  of  body  temperature  into  relation  with  the 
reduction  of  the  metabolism,  as  is  the  case  in  myxedema.  Everything 
speaks  for  the  point  of  view  that  also  in  hypophysial  dystrophy  the  vegeta- 
tive functions  proceed  slower  than  in  normal  individuals. 

It  seems,  however,  almost  as  though  in  hypophysial  dystrophy  the  regu- 


298  THE    DISEASES    OF    THE    HYPOPHYSIS 

lating  of  temperature  may  under  circumstances  show  an  especial  lability. 
V.  Frankl-Hochwart  has  already  pointed  out  the  fact  that  in  tumors  of  the 
hypophysis  without  acromegaly  sometimes  hyperthermia  occurs.  Ciishing 
further  reports  that  the  injection  of  glandular  extract  into  hypophysioprivic 
animals  leads  to  an  increase  of  temperature,  while  in  normal  animals  this 
increase  after  the  injection  never  occurs.  Ciishing  has  used  this  "  thermoreac- 
tion"  as  a  diagnostic  aid,  and  assumes  a  state  of  hypophysial  insufhciency 
in  all  cases  of  pituitary  disease  in  which  the  increase  of  temperature  occurs 
after  the  injection  of  2  cc.  of  a  5  per  cent,  extract  of  the  anterior  lobe  of  the 
ox  hypophysis. 

Kahn  and  myself  in  studies  on  tetany  have  several  times  seen  in  the  acute 
stages,  after  the  injection  of  2-4  cc.  of  pituitrinum  glandulare  of  Parke, 
Davis  0°  Co.  that,  as  was  shown  especially  actively  in  investigations  on 
respiratory  metabolism,  there  occurred  an  increase  of  temperature  to  over 
38°.  Lately  Bernstein  and  myself  instituted  experiments  on  twenty  indi- 
viduals, some  of  whom  were  normal  and  some  affected  with  various  diseases, 
injecting  them  subcutaneously  with  2  cc.  and  eventually  10  cc.  of  the  glandu- 
lar extract.  Never  did  there  occur  an  increase  of  temperature.  In  one 
case  of  very  chronic  acromegaly,  the  experiment  was  negative  (case  Ad,  Ob- 
servation XXIX).  We  saw,  on  the  contrary,  in  case  F,  Observation 
XLIV,  which  will  later  be  reported  in  detail,  no  distinct  action  after  the 
injection  of  4  cc,  but  later  on  repetition  with  5  cc.  twice  an  increase  of 
temperature  of  more  than  2°. 

I  would  not  attempt  an  explanation  of  this  remarkable  phenomenon. 
More  extensive  observations  are  necessary  to  establish  the  diagnostic 
significance  of  the  reaction. 

Almost  regularly  in  h)'pophysial  dystrophy  are  found  alterations  of  the 
blood  picture. 

I  have  carried  out  investigations  as  to  this  point  for  years,  at  first  in 
collaboration  with  Dr.  Bertelli,  in  a  series  of  cases  at  the  clinic. 

Through  the  kindness  of  Prof.  v.  Frankl-Hochwart^  we  were  permit- 
ted to  examine  some  of  the  cases  reported  by  him.  I  cite  the  following 
observations: 

Observation  XXXIX. — W.,  twenty-six  years  old,  typical  case  of  hypophysial  dystro- 
phy. Examination  of  the  blood  in  July,  1907.  At  that  time  diplopia,  reduction  of  the 
visual  power,  bitemporal  hemianopsia;  since  the  nineteenth  year  of  life  no  erections,  and  no 
libido,  genitalia  infantile,  pubic  hair  and  axillary  hair  almost  entirely  absent.  X-ray 
shows  widening  of  the  sella  turcica. 

Alimentary  glycosuria  (100  gm.  dextrose),  negative. 

Erythrocytes,  4,800.000. 

Leucocytes,  5600 

Hemoglobin,  7.5  g. 

Dec,  1907,  operation  by  Prof.  v.  Eisdsberg,  after  which  improvement  of  the  power  of 
vision  and  of  headache. 


HYPOPHYSIAL    DYSTROPHY  299 

March,  1908:  erythrocytes,  5,260,000 
Leucocytes,  7500 
Hemoglobin,  8.2  g. 

Observation  XL. — D.,  twenty-one-year-old  man,  Nov.,  1909,  for  ten  years  gradually 
occurring  headaches  and  vomiting.  For  eight  years,  diminution  of  the  visual  acuity. 
At  that  time  temporal  hemianopsia.  Pronounced  obesity,  genitalia  infantile,  pubic  and 
axillary  hairs  absent.  Destruction  of  the  body  of  the  sphenoid  bone  and  of  the  dorsum 
sellae.  June,  1907,  operation  hy  Prof.  v.  Eiselsherg.  Cyst  of  the  hypophysis,  histologically 
carcinoma.  Improvement  of  the  power  of  vision.  May,  1908,  occurrence  of  erections. 
August,  1908,  voice  deeper.  October,  1909,  sparse  hairiness  in  the  axillae  and  on  the 
pubes.  Eye-findings  as  formerly.  No  erections.  Body  weight  now  62},i  kg.  (formerly 
65.2  kg.). 

Blood  count:  Erythrocytes,  4,200,000 
Hemoglobin,  9.4  gm. 
Leucoc3^tes,  8200 

Polymorphonuclear  leucocytes,  52  per  cent. 
Large  mononuclears,  7  per  cent. 
Lymphocytes,  37  per  cent. 
Eosinophiles,  4  per  cent. 
Observation  XLI. — 0.  M.,  girl,  twenty-three  years  old,  Dec.  3,  1909.     No  hereditary 
taint,  always  well,  except  that  from  childhood  she  has  been  strikingly  pale.     One  menstrua- 
tion at  the  age  of  twelve  years,  she  mensturated  regularly  between  the  ages  of  fourteen 
and  nineteen  yeais,  then  sudden  cessation,  with  normal  genitalia.     Now  and  then  mod- 
erate pressure  in  the  head.     March,  1909,  influenza,  after  which  dietary  treatment  with- 
out rest  in  bed.     Increased  in  weight  8.5  kg.  (from  53.5  to  62  kg.).     At  the  beginning  of 
October,  1909,  blurring  before  the  left  eye,  since  which  time  things  have  remained  station- 
ary.    No  headache,  no  vertigo,  no  vomiting,  no  fainting-spells,  no  insomnia,  no  yawning, 
no  disturbance  of  movements,  no  rhinorrhea. 

Eyes. — 0.  D.  normal,  O.  S.  6/12  fundus  normal,  L.  P.  temp,  scotoma  for  white.  Bi- 
temporal color  hemianopsia.  The  nerve  findings  negative.  Internal  findings  and  urinary 
findings  negative.  Moderate  struma,  patient  is  of  medium  height,  strikingly  pale,  does 
not  make  an  impression  of  corpulency,  except  that  a  rather  large  collection  of  fat  is  present 
on  the  abdomen.  Hair  of  the  head  abundant,  axillary  and  genital  hairiness  normal.  The 
fingers  seem  somewhat  pufl'ed  up  and  thickened.  Slight  development  of  hair  on  the  upper 
lip  and  chin. 

X-ray  (Docent  Dr.  Keinbock) :  Sella  turcica  appreciably  enlarged,  especially  below  and 
behind.     The  dorsum  sells  is  visible  only  as  a  small  bolt-shadow  strip. 

Weight  61  kg.     Temperature  on  Dec.  6  and  Dec.  7  varied  between  36.2  and  36.7. 
Blood  count:  Erythrocytes,  4,464,000 
Hemoglobin  (according  to  Salili),  70  per  cent. 
Leucocytes,  5900 

Polymorphonuclear  leucocytes,  60.8  per  cent. 
Lymphocytes,  30.8  per  cent. 
Large  mononuclear,  4  per  cent. 
Eosinophiles,  4  per  cent. 
Mast-cells,  0.4  per  cent. 
Observation  XLII. — K.  L.,  seventeen  years  old.     Dec,  1909.     Up  to  this  time  has 
not  yet  menstruated,  since  the  autumn  of  1906  headaches,  decrease  of  visual  power  and 
rapid  increase   of  body  weight.     Bitemporal  hemianopsia.     Genitals  infantile.     Axil- 
lary hair  poorly  developed.     X-ray  shows  dilatation  of  the  sella. 
Operation  by  Prof.  v.  Eiselsberg. 


300 


THE    DISEASES    OF    THE    HYPOPHYSIS 


Blood  count,  Dec,  iqoq:  Erythrocytes,  4,680,000 
Hemoglobin,  9.34  gm. 
Leucocytes,  9400  of  which: 
Polymorphonuclear  neutrophiles,  56.3  per  cent. 
Lymphocytes,  31.3  per  cent. 
Large  mononuclears,  7.9  per  cent. 
Eosinophiles,  ^.;i  per  cent. 
Mast-cells,  1.2  per  cent. 

I  tabulate  these  observations  together  with  those  of  the  other  observations 
reported  in  detail  in  this  book,  in  the  following  list: 


Observation 


Observation    XXXIX,   W, 
before  operation, 
four  months  after  opera- 
tion. 

Observation  XL,  D,  two 
and  one-fourth  3'ears 
after  operation. 

Observation  XLI,  Olga  M. 

Observation  XLII,  K.  L., 
after  operation. 

Observation  XXXIV,  S.... 
about  5  wks.  after  opera- 
tion. 

Observation  XLIII,  P 

Observation  XLI V,  F 

Observation  XXXVIII,  Ka 

Observation  XLV,  Gr 

later 

Observation  XXXVI,  G.W. 


Erythrocytes 


Hb 


Leucocytes 


4,600,000 
5,260,000 
4,200,000 


4,460,000 
4,680,000 


7-5  gm. 
8.  2  gm. 
9.4  gm. 


70  per  cent. 
9-34  gm. 

75  per  cent. 


5,600 

7,500 
8,200 


5,900 
9,400 

8,400 


5,000,000 
4,680,000 


4,800,000 
3,300,000 
4,600,000 


57  per  cent. 
45  per  cent. 
84  per  cent. 


10,000 

5,900 

6,500 

15,000 

13,900 

7,800 


Neutro- 
philes 


52.0 

60.8 
56.5 

56.1 
71  .0 


64.0 
65.0 
62.0 
58.0 

74-1 


Eosino- 
philes 


4.0 


4.0 

3-3 


3-2 


7.0 
9.0 


Lately  there  are  observations  of  Borchardt  in  four  cases,  in  which  he  found 
the  red  blood  cells  to  be  somewhat  reduced,  the  leucocytes  at  the  lower  limits 
of  normal,  the  neutrophiles  mostly  markedly  reduced,  the  eosinophiles 
somewhat  high,  in  one  case  up  to  11.5  per  cent. 

If  we  summarize  all  these  cases,  we  find  that  there  is  mostly  only  a  slight 
reduction  of  erythrocyte  count  or  none  at  all  (or  even  after  operation  an  in- 
crease in  the  number  of  erythrocytes),  while  in  all  cases  there  was  a  not  in- 
appreciable reduction  of  hemoglobin;  the  leucocyte  count  is  often  diminished, 
and  in  one  case  increased.  Most  important  is  the  result  of  the  differential 
count  of  the  leucocytes.  Almost  in  all  cases  the  number  of  neutrophilic 
cells  is,  relatively,  markedly  reduced,  while  that  of  the  mononuclears,  and 
especially  the  lymphocytes,  relatively  and  also  absolutely  raised.  The 
eosinophiles  show  in  many  cases  an  appreciable  increase.  After  operation 
the  leucocyte  picture  may  revert  to  normal  (Observation  Si,  XXXIV). 
In  two  cases  (Observations  D  and  K.3^.)  there  were,  however,  marked  mono- 


HYPOPHYSIAL   DYSTROPHY  3OI 

nucleosis  after  the  operation.  In  these  cases  the  hemoglobin  remained 
markedly  reduced  after  the  operation.  Perhaps  the  mononucleosis  is  the  ex- 
pression of  a  slight  grade  of  status  lymphaticus.  The  blood-count  in  general, 
as  far  as  mononucleosis  and  poverty  in  hemoglobin  are  concerned,  is  similar 
to  that  of  myxedema. 

I  enter  more  in  detail  into  the  consideration  of  a  symptom  which  up  to 
the  present  has  not  been  sufhciently  regarded  in  the  differential  diagnosis. 
I  refer  to  the  inhibition  of  growth.  Already  v.  Frankl-Hochwart  emphasized 
that  the  cases  of  tumor  of  the  hypophysis  without  acromegaly  in  youth 
almost  always  affect  small  individuals.  Almost  in  all  cases  in  which  the 
disease  began  in  the  years  between  childhood  and  adolescent  hfe  is  remain- 
ing behind  in  growth  reported.  I  here  quote  what  I  have  been  able  to  find 
in  this  subject: 

Case  of  Berger. — Began  at  twelve  years. 

Case  I  of  BycJiowski. — K.  L.,  seventeen-year-old  girl,  very  small,  132 
cm.  tall  (operated  on  by  v.  Eiselsberg),  cyst  of  the  hypophysis. 

Case  2  of  Bychowski. — Reported  very  briefly.  Growth  ceased  at  the 
age  of  thirteen  years,  132  cm.  tall. 

Case  2  of  Nazari. — Normal  development  up  to  between  the  sixth  and 
seventh  years,  then  remaining  behind  in  growth;  at  twenty  years  of  age, 
125  cm.  tall. 

Case  I  of  Bahonneix  and  Paisseau. — From  eleven  and  one-half  years 
on,  height  remained  stationary. 

Case  I  of  Erdheim. — Twenty-year-old  woman,  "body  very  small." 

Case  of  Zbllner. — One  hundred  forty-five  centimeter  tall  individual. 

Case  of  Uhthoff. — Dwarfism  with  bitemporal  hemianopsia. 

Case  I  of  Ettore  Levi.- — Twenty-and-one-half-year-old  woman,  from  ten 
years  old  on  cessation  of  growth,  130  cm.  tall,  lower  length  71  cm.,  geni- 
talia infantile,  sella  turcica  considerably  widened. 

Case  I  of  Bartels. — Twenty-one-year-old  man,  cessation  of  growth  at 
the  fourteenth  year. 

Case  2  of  Bregman  and  Steinhaus. — Seven-year-old  girl,  "relatively 
small." 

Case  of  Mixter  and  Quackenboss. — Twenty-seven-year-old  man  who 
looks  as  if  he  were  eighteen  years  old,  enlargement  of  the  sella,  operation. 
Epithel.  congen.  of  the  hypophysis  with  cystic  degeneration. 

Case  of  Kilmmel. — Twenty-three-year-old  man,  looks  as  if  he  were 
fourteen  years  old,  no  obesity. 

Case  of  Leman  and  Van  Wart. — Twenty-four-year-old  woman,  infantile. 

Case  of  Bournier. — Twenty-six  year-old  man,  125  cm.  tall,  eye  disturb- 
ances since  his  eighth  year,  disturbance  of  growth  since  his  tenth  year. 

Case  of  Remiie. — Cessation  of  growth  at  the  same  time  as  the  appearance 
of  manifestations  of  hypophysial  tumor. 


302  THE    DISEASES    OF    THE    HYPOPHYSIS 

Own  Observation  XXXIII  (L). — One  hundred  thirty-one  centimeters 
tall  since  ten  years  old.     Has  not  grown  for  two  years. 

Own  Observation  XXXIV  (Si). — Sixteen-year-old  girl,  145  cm.  tall. 

Own  Observation  XXXVII  (Sch). — At  the  beginning  very  marked  growth, 
cessation  of  growth  at  thirteen  years  of  age. 

Also  the  cases  of  dystrophia  adiposo-genitalis  with  brain  processes  in 
which  a  limitation  of  the  function  of  the  hypophysis  may  be  suspected,  show 
the  inhibition  of  growth. 

Case  of  E.  MiiUer. 

Case  I  of  Goldstein. — Cessation  of  growth  at  the  fifth  year. 

Also  Case  3  of  Goldstein  is  called  "small."  Both  were  diagnosed  serous 
meningitis. 

Case  2  of  Xeurath. — Scarlet  fever  at  seven  years  of  age,  shortly  afterward 
cessation  of  growth;  at  ten  years  of  age  109  cm.  (instead  of  130  cm.),  prob- 
ably hydrocephalus  due  to  meningitis  (see  later,  case  Fr,  ObservatioQ 
XLIV).^ 

The  following  case  may  be  regarded  as  a  case  sui  generis  of  Iiypophysial 
dwarfism : 

Case  of  Jutaka  Kon. — A  thirty-seven-year-old  "dwarfishy  built  man" 
(147  cm.  tall),  could  not  visit  the  school  on  account  of  weakness  of  the  eyes. 
Now  and  then  epileptic  attacks,  coarse,  glittering  face,  skin  dry,  lately  in- 
creasing mental  slowness,  no  hairiness  on  the  mons  Veneris,  on  the  scrotum, 
or  near  the  lips.  Genitalia  entirely  infantile.  Autopsy  showed  a  slight  hy- 
poplasia of  the  thyroid  gland  and  an  enormous  calcified  tumor  of  the  in- 
fundibulum,  that  histologically  was  a  teratoma.  The  teratoma  has  existed 
since  earliest  youth,  it  was  ''evidently  congenital."  * 

The  case  of  Benda  was  that  of  a  thirty-eight-year-old  dwarf.  There  was 
found  a  hazelnut-sized  teratoma  of  the  hypophysis.  The  remnant  of  the 
gland  was  atrophic,  the  genitalia  were  infantile.  Here  hkewise  there  was  a 
teratoma,  so  that  it  is  probable  that  it  had  existed  since  youth  and  was  re- 
sponsible for  the  dwarfism  and  the  genital  dystrophy. 

The  case  of  Woods  Hutchinson  is  correctly  regarded  by  Breus  and 
Kolisko  as  chondrodystrophy. 

In  the  case  of  Hagenbach  (sarcoma  of  the  hypophysis  in  an  individual 
103  cm.  tall)  the  connection  between  the  growth  disturbance  and  the  tumor 
of  the  hypophysis  is,  as  the  author  points  out,  hard  to  show,  as  it  is  not  known 
when  the  tumor  began  to  form. 

Aschner  describes  a  case  of  dwarfism  which  he  regards  as  hypophysial — 
entirely  incorrectly.  In  this  case  there  does  not  exist  a  single  symptom  that 
points  to  this  hypophysis.     I  regard  this  case  as  a  true  infantilism. 

The  case  of  Hueter,  quoted  by  Aschner,  is  quite  uncertain.  Hiieter  him- 
self is  of  the  opinion  that  the  tuberculous  disease  of  the  hypophysis,  in  the 
forty-two-year-old  woman,  is  of  recent  date,  and  therefore  has  nothing  to 


HYPOPHYSIAL    DYSTROPHY 


303 


do  with  the  dwarfism.     In  this  case  the  sexual  organs  were  well  developed. 
This  speaks  against  the  existence  of  the  hj-pophysial  affection  since  youth. 

In  May,  191 1, 1  obser\'ed  a  case  that  perhaps  belongs  to  this  categor\-. 
Observation  XLHI.—^l.  S.  P.,  forty-one  years  old,  from  Palestine.  Entered  the 
clinic  May,  191 1.  Family  history  good.  The  patient  states  that  his  genitals  have 
been  of  the  present  size  since  childhood.  In  spite  of  the  fact  that  the  penis  is  diminu- 
tively small,  it  is  subject  to  erections.  First  coitus  at  the  age  of  twenty-two  years. 
Coitus  was  then  practised  several  times  a  month  up  to  the 
twenty-sixth  year.  The  pleasurable  sensation  was  very 
great,  but  there  had  never  occurred  an  ejaculation.  Also 
now  the  penis  sometimes  becomes  erect,  the  erections  last- 
ing for  six  to  eight  hours:  they  are  associated  with  intense 
voluptuous  sensations.  AVe  ourselves  saw  such  an  erection. 
the  penis  measuring  3  cm. 

For  three  j^ears  the  patient  has  suffered  with  violent 
right-sided  headaches.  There  exists  a  slight  right-sided 
ptosis  and  paresis  of  the  superior  oblique  and  inferior  oblique 
muscles  with  diplopia. 

The  patient  is  154  cm.  tail:  span  width  172  cm.,  lower 
length  97  cm.;  he  is  somewhat  fat,  and  there  are  abundant 
accumulations  of  fat  on  the  hips  and  on  the  mons  A'eneris. 
Hairs  of  the  beard  are  entirely  absent,  and  there  is  very  sparse 
hairiness  of  the  mons  Veneris  and  the  axillce.  The  penis  is 
diminutive,  and  there  is  a  sHght  hypospadias  .  The  scrotum 
is  very  small.      There  is  bUateral  cryptorchidism. 

X-ray.  Both  cK\d  sharpened,  entrance  to  seUa  widened. 
Floor  of  sella  not  essentially  deepened. 

Examination  of  the  eye-grounds;  both  papillae  present  a 
washed-out  appearance,  old  neuritis. 
Blood  count:  Erythrocytes,  5,000,000 
Hemoglobin,  65  per  cent.,  according  to  Salili 
Leucocytes,  10,000,  of  which: 
Polymorphonuclear  neutrophUes,  50.1  per  cent. 
Large  mononuclears,  15.0  per  cent. 
Lj'-mphocytes,  24.4  per  cent. 
Eosinophiles,  0.5  per  cent. 
Adrenalin  subcutaneouslv  Co. 001  gm.").  no  glvcosuria. 


Fig.  57. — Teratoma  of_the 
h\-pophysis. 


At  first  I  regarded  this  case  as  a  eunuchoid,  in  which  a  certain  function 
of  the  genitaha  was  retained.  Also  the  proportioning  of  the  body  seems  to 
me  to  speak  to  the  same  eft'ect.     Against  pure  dysgenitalism  speaks  however : 

1.  The  disturbance  in  growth  (both  patient's  parents  are  large  in- 
dividuals) . 

2.  The  disturbance  of  eye  muscles,  the  s\Tnptoms  of  brain  pressure,  and 
the  X-ray  findings. 

As  the  genital  disturbance  had  action  already  in  earliest  youth,  the  eye- 
muscle  disturbance  first  becoming  apparent  only  about  four  years  ago,  we 
must  think  of  a  gradually  developing  hypophysial  tumor.  This  may  be  a 
teratoma. 


304 


THE    DISEASES    OF    THE    HYPOPHYSIS 


Lately  Sprinzds  has  shown  a  case  before  the  Wiener  Gesellschaft  der 
Arzte  [Vienna  Association  of  Physiciansl  that,  on  account  of  the  interest  it 
affords,  I  shall  describe  in  detail.  It  was  that  of  a  young  man  seventeen 
years  old.  In  the  third  year  of  his  Ufe  after  a  knock  he  sustained  spasms, 
probably  of  a  toxic  character.  Since  that  time,  great  thirst  and  polyuria. 
Since  the  fifth  year  of  life  cessation  in  growth,  sometimes  headache,  intelli- 
gence well  developed,  gay  temperament.  Height  io6  cm.,  circumference  of 
head  52.5  cm.,  physiognomy  that  of  a  mature  individual,  skin  soft,  smooth, 
rough  and  scaly  only  at  certain  places,  dry,  no  secretion  of  sweat.  Abun- 
dant deposition  of  fat  on  chest  and  abdomen  (mons  Veneris?),  no  hairiness 
on  the  trunk.     Voice  childish,  several  of  the  teeth  belonging  to  the  milk 


Fig.  5S. — Genitalia  of  Observation  XLIll. 


set,  genitals  correspond  to  those  of  a  six-year-old  boy  (erections  were  ob- 
served, however).  Amount  of  urine  3500-4000  cm.,  specific  gravity  1002- 
1003.  Ossification  relations  correspond  to  those  of  a  four-and-one-half 
to  five-year-old  child.  Sella  turcica  shows  no  tendency  to  bone  destruc- 
tion. "A  shadow  focus  coming  into  the  sella  from  above,  and  filUng  out 
the  sella  Hke  a  bolt,  leaving  a  light  zone  free,"  no  disturbance  of  vision. 
Diagnosis  benign  tumor  of  the  hypophysis  or  in  the  vicinity  of  the  hy- 
pophysis, probably  teratoma. 

I  quote  the  follo^^^ing  as  a  further  case  of  marked  disturbance  in  growth, 
apparently  due  to  a  destruction  of  function  of  the  h^-pophysis.  We  shall 
find  that  it  will  interest  us  later,  in  the  consideration  of  the  proportioning  of 
the  body  and  the  behavior  of  ossification. 


HYPOPHYSIAL   DYSTROPHY 


305 


Observation  XLIV. — Case  F.,  fifteen  years  old.  Entered  the  clinic  September, 
1912.  The  mother  of  the  patient  states  that  the  birth  was  normal,  but  that  she  cannot 
say  with  certainty  when  the  growth  disturbance  first  began;  but  that  there  was  rachitis 
at  the  eighth  year.  The  child  walked  late.  The  abdomen  at  that  time  was  distended- 
At  all  events  it  is  to  be  supposed  that  the  growth  disturbance  goes  back  very  far.  When 
the  mother  was  asked  concerning  fat  stools,  she  answered  that  these  had  existed  as  long  as 
she  can  remember.  Measles  at  six  years  of  age.  In  early  childhood,  patient  had  frequent 
sweats.  Of  late  years,  he  has  become  thin,  and  has  felt  very  weak;  he  became  silent 
and  melancholy.  He  complains  of  violent  vertigo  and  of 
headache.  For  three  weeks  diarrheal  evacuations,  that  have 
seemed  fatty.  The  development  of  the  intelligence  was  ap- 
parently normal. 

The  boy  measures  121  cm.,  the  span  width  is  121  cm., 
lower  length  (from  ant.  sup.  spine  to  internal  malleolus)  63 
cm.  The  skull  has  the  form  of  a  tower;  the  greatest  circum- 
ference measures  613^^  cm.  The  tubera  frontalia  project  to 
a  degree,  no  saddle-nose,  the  teeth  are  very  bad,  the  incisor 
teeth  are  much  ridged,  certain  teeth  belonging  to  the  milk 
set.  Genua  valga.  The  color  of  the  face  is  pale,  the  skin  of 
the  entire  body  is  white,  remarkably  delicate,  quite  feminine. 
The  patient  is  thin,  but  nevertheless  there  are  deposits  of 
fat  on  the  hips  and  nates,  in  the  hypogastric  regions  and 
somewhat  more  distinctly  on  the  mons  Veneris.  No  rosary 
formation;  no  bending  of  the  extremities.  No  glands  pal- 
pable. Lung-findings  normal.  The  heart  sounds  are  clear, 
after  several  sittings  extrasystoles.  Examination  with  the 
electrocardiogram  shows  complete  dissociation. 

The  development  of  the  genitalia  has  remained  behind  to  a 
marked  degree.  The  penis  is  small,  prepuce  well  developed. 
The  inguinal  canals  are  pervious  for  two  fingers,  the  testicles 
lie  in  the  inguinal  canal  and  come  down  a  little  only  on 
marked  coughing.  They  are  about  the  size  of  beans  and 
very  soft;  the  paradidymis  is  hardly  delimitable.  The  hairi- 
ness on  the  trunk  and  genitalia  is  entirely  absent. 

Wassermann  reaction  negative.  Alimentary  glycosuria 
(200  gm.  dextrose)  negative. 

Blood  count:  Erythrocytes,  4,800,000 

Hemoglobin,  45  per  cent. 

Leucocytes,  5900  of  which: 

Polymorphonuclear  leucocytes,  64  per  cent. 

Lymphocytes,  25  per  cent. 

Large  mononuclears,  43^^  per  cent. 

Eosinophiles,  ^y^  per  cent. 

Mast-cells,  i  per  cent. 
The  eye  examination  shows  prominent  eye-balls,  oblique  palpebral  fissures,  dilated  pupils, 
nerves  pale,  well  delimited;  the  vessels,  especially  the  veins  and  the  peripheral  and  muscular 
branches  are  appreciably  convoluted  without  dilation,  old  neuritis  (?)  {Docent  UlbricJi). 
X-ray.  Skull  strikingly  large  and  high;  hydrocephalus,  sella  of  normal  dimensions, 
dilated  only  at  its  entrance,  its  contour  retained.  The  dilatation  of  the  entrance  to  the 
sella  is  perhaps  only  a  partial  manifestation  of  the  hydrocephalic  extension  of  the  skull 
{Docent  Schilller) . 


Fig. 


59- 


3o6  THE    DISEASES    OF    THE    HYPOPHYSIS 

The  examination  of  the  respiratory  gas  exchange  {Dr.  Bernselin)  shows: 

CO9  elimination  5.14  \    .  .  ,,  ,,  •         u  ^• 

(  Average  01  three  well-concurring  observations. 
O2  consumption  6.1 1  J 

The  temperature  is  instituted  at  a  low  level,  ordinarily  between  36°  and  36.4°. 

Injection  of  4  cc.  pituitrinum  glandulare  intramuscularly  shows  slight  increase  of 
temperature,  up  to  37°. 

Nov.  6.  Injection  of  5  cc.  pituitrinum  glandulare  intramuscularly  at  9  a.m.  causes  an 
afternoon  rise  of  temperature  to  38.5°  (4  o'clock).  At  8  o'clock  still  38°.  On  the  next 
morning  temperature  again  36.2°,  no  subjective  manifestations. 

The  investigation  of  the  gaseous  exchange  after  the  injection  shows  a  very  marked 
decrease  of  the  carbonic  acid  production  and  the  oxygen  consumption.  There  was  appre- 
ciable increase  of  respiratory  quotient. 

Repetition  of  the  experiment  on  Nov.  13  with  5  cc.  of  pituitrinum  glandulare  (intra- 
muscularly) brought  about  an  increase  of  temperature  to  over  38°C. 

The  amount  of  urine  varied  between  2000  and  4000  cc.  Correspondingly  the  specific 
gravities  varied  between  loio  and  1006,  exceeding  loio  very  rarely. 

At  the  beginning  several  bowel  movements  daily,  later  only  one  or  two.  The  stools  are 
mostly  more  or  less  brothy,  whitish,  glistening  like  fat,  containing,  as  is  shown  on  micro- 
scopical examination,  many  needles  of  soap  fatty  acids  and  of  neutral  fat. 

Appetite  and  general  condition  improve  rapidly,  also  a  rapid  increase  of  body  weight 
from  24  kg.  to  321.^  kg.  in  the  course  of  five  weeks,  with  distinct  prominence  of  the  abnor- 
mal distribution  of  fat  on  the  buttocks,  mons  Veneris,  etc. 

The  intelligence  of  the  boy  is  in  general  well  developed,  temperament  is  gay.  The 
complaints  as  to  headache  are  less. 

X-ray  examination  of  the  hand  shows  marked  developmental  disturbance  of  ossifica- 
tion. The  development  of  the  bone-nuclei  about  corresponds  with  that  of  an  eight-  to 
nine-year-old  boy. 

In  this  case  we  are  dealing  with  a  chronic  hydrocephalus  that  apparently 
has  led  since  earHest  youth  to  disturbance  of  the  function  of  the  hypophysis 
through  pressure  on  the  entrance  to  the  sellas.  For  the  disturbance  of  hypo- 
physial function  speak:  i.  The  growth  disturbance  and  the  disturbance  in 
ossification  and  dentition.  2.  The  genital  dystrophy  with  the  typical  obesity. 
3.  Perhaps  the  "  thermoreaction."  Whether  there  exists  here  a  disturb- 
ance in  metabolism  we  cannot  decide,  as  there  are  no  values  of  comparison 
with  normal  individuals  of  the  corresponding  size  and  weight.  Fitting  in 
with  the  diagnosis  are  also  the  behavior  of  the  carbohydrate  metabolism, 
the  blood-count,  the  hypothemia,  and  the  sHght  degree  of  polyuria. 

There  are  as  yet  no  statements  in  the  literature  as  to  the  proportioning 
of  the  skeleton  and  the  ossification  conditions.  In  the  study  of  my  cases  I 
made  certain  observations  that  seem  to  me  important  for  the  differential 
diagnosis  of  the  hypophysial  dystrophy  from  the  primary  genital  dystrophy. 

The  proportioning  is  sometimes  more  of  an  infantile,  sometimes  more  of  a 
eunuchoid  type,  that  is,  in  the  latter  case  the  lower  length  considerably  ex- 
ceeds the  upper  length.  In  a  case  of  Ettore-Levi  the  total  length  was  130  cm., 
the  lower  length  71  cm.  In  my  case  L,  Observation  XXXIII,  the  total 
length  was  131  cm.,  the  distance  from  the  anterior  superior  spine  to  the  in- 


HYPOPHYSIAL   DYSTROPHY 


307 


Fig.  60. — Sella  turcica  of  Observation  XLIV 


3o8 


THE    DISEASES    OF    THE    HYPOPHYSIS 


Fig.  6i. — X-ray  picture  of  hand  of  Observation  XLIV. 


HYPOPHYSIAL    DYSTROPHY 


309 


Fig.  62. — X-ray  picture  of  the  hand  of  a  normal  individual  of  the  same  age  as 

Observation  XLIV. 


3IO  THE    DISEASES    OF    THE    HYPOPHYSIS 

terior  malleolus  69  cm. ;  also  in  case  Si,  Observation  XXXIV.  the  lower  length 
is  not  essentially  greater  than  the  upper  length.  Quite  infantile  are  the 
dimensions  in  case  Fr,  Observation  XLIV.  On  the  contrary  in  case  Sch, 
Observation  XXX\'II,  the  lower  length  again  distinctly  exceeds  the  upper 
length,  as  it  does  also  in  case  P,  Observation  XLIII.  It  seems  to  me  that 
here  two  factors  are  working  in  opposite  directions.  The  one  is  a  genital 
disturbance,  which  brings  about  tallness  and  excess  of  the  lower  length 
over  the  upper  length,  the  other  is  a  growth  disturbance  conditioned  by  the 
falling  out  of  hypophysial  function.  According  as  the  one  or  the  other 
predominates  do  the  proportions  approach  the  eunuchoid  or  the  infantile 
type.     In  the  severest  cases  it  is  indeed  mostly  infantile.^ 

A  distinct  difference  exists  in  the  ossification  conditions  of  h\ipophysial 
dystrophy  and  eunuchoidism.  As  we  shall  see  later,  in  the  latter  only  the 
epiphysial  closure  is  disturbed;  the  development  of  the  bone  nuclei,  however, 
according  to  what  has  been  observed  up  to  the  present,  is  not  essentially 
delayed.  But  the  delay  in  the  epiphysial  closure  is,  however,  of  a  high  grade 
and  lasts  until  late  life. 

How  are  the  conditions  in  hypophysial  dystrophy?  Case  W.  (Observa- 
tion XXXIX)  reported  by  v.  Frankl-Hochwart  and  v.  Eisehberg,  was,  when  I 
examined  him,  twenty-seven  and  one-half  years  old.  The  first  symptoms  had 
set  in  at  nineteen  years  of  age;  the  condition  of  ossification  was  entirely 
normal.  In  an  eunuchoidism  that  had  set  in  so  late  certain  epiphysial  junc- 
tures would  have  remained  open,  and  there  would  have  been  an  additional 
growth  of  some  centimeters.  In  case  L.  (Observation  XXXIII)  and  in 
case  Si  (Observation  XXXIV)  the  behavior  of  ossification  approached  the 
normal. 

Quite  otherwise  are  the  relations  in  the  cases  in  which  the  severe  dis- 
turbance of  growth  sets  in  early.  In  Case  F.  (Observation  XLII)  the 
development  of  the  bone  nuclei  corresponded  to  that  of  an  eight-  to  nine- 
year-old  boy  rather  than  to  that  of  a  fifteen-year-old  boy.  I  refer  to  the 
X-ray  picture  of  this  case  as  compared  with  that  of  a  normal  fifteen-year-old 
boy  (Figs.  61  and  62). 

Hence  in  these  cases  the  growth  disturbance  is  similar  to  that  in  hypo- 
thyroidism. From  the  literature  I  can  quote  only  the  case  of  Bournier, 
which  shows  that  in  the  high  degrees  of  growth  disturbance  also  the  closure 
of  certain  epiphyses  is  markedly  delayed.  In  the  twenty-six-year-old  patient 
the  proximal  epiphyses  of  the  phalanges  and  of  the  first  metacarpal  bones, 
and  the  distal  epiphyses  of  the  ulna  and  radius,  are  still  open.  Finally  the 
case  reported  by  Sprinzcl  in  which  ossification  has  remained  behind  much 
farther  than  in  my  case  F. 

From  all  this  seems  to  be  inferred,  that  the  disturbance  of  ossification  in 
light  grades  of  hypophysial  dystrophy  is  not  very  pronounced,  in  severer  grades 
1 1  refer  to  Chapters  X  and  XII. 


HYPOPHYSIAL  DYSTROPHY  31I 

it  affects  in  the  same  manner  the  occurrence  of  the  hone-nuclei  and  of  the  epiphysial 
closure,  while  in  pure  eunuchoidism  the  epiphysial  closure  is  indeed  involved, 
hut  this  distiirhance  lasts  until  late  in  life. 

To  the  above-described  manifestations  is  added,  according  to  the  process 
that  damages  the  hypophysis,  a  series  of  manifold  symptoms.  Most  common 
are  tumor  symptoms,  such  as  tend  to  appear  in  tumors  of  the  middle  fossa  of 
the  skull.  Most  frequent  are  headaches,  that  for  the  most  part  are  not  lo- 
calized; also  disturbances  of  vision  (bilateral  hemianopsia  or  simple  amblyo- 
pia and  amaurosis,  genuine  atrophy,  and  not  rarely  choked  disc).  First 
there  appears  bilateral  hemianopsia  for  colors,  and  only  later  for  white;  in 
quite  rare  cases  there  may  occur  a  homonymous  hemianopsia  owing  to  de- 
struction of  the  tract  by  a  tumor  (a  case  of  O.  Hirsch's) ;  in  addition  vertigo, 
insomnia,  frequent  yawning  (little  sleep  at  night  however),  apathy,  finally 
psychic  disturbances,  sometimes  also  nasal  discharge  of  cerebrospinal  fluid. 
With  these  symptoms  are  associated  paresis  of  the  eye-muscles,  disturbances 
of  smell,  taste,  and  hearing,  vomiting,  manifestations  of  a  hydrocephalus, 
bilateral  clonic  twitching,  eventually  paresis  of  the  extremities.  Exophthal- 
mus  may  also  occur,  owing  to  penetration  of  the  tumor  into  the  orbit  (case 
of  Pechkranz) . 

According  to  the  nature  of  the  picture,  the  X-ray  examinations  show 
widening  of  the  introitus  to  the  sella  with  destruction  of  the  clinoid  processes 
and  eventually  with  deepening  of  the  sellar  floor  (especially  in  tumor  of  the 
hypophysis),  but  in  extrasellar  processes  sharpening  of  the  clinoid  processes, 
and  only  later  destruction  of  these  {Erdheim  and  Schuller),  deepening  of  the 
impressiones  digitatse  in  youthful  individuals,  eventual  enlargement  of  the 
skull  and  essential  thinning  of  its  bony  walls. 

Noticeable,  finally,  are  certain  alterations  of  the  psyche,  v.  Frankl- 
Hochwart  emphasizes  that  in  these  patients  there  is  a  remarkable  restlessness 
and  resignation,  and  that  in  spite  of  the  existing  headache  they  often  show 
a  gay  temperament.  In  youthful  individuals,  at  all  events,  this  gay  tempera- 
ment (case  F.,  Observation  XLIV,  and  the  case  of  Sprinzel)  contrasts  mark- 
edly with  the  stupidity  and  moroseness  of  hypothyroidism  in  childhood. 
In  many  cases  of  hypophysial  dystrophy  there  may,  of  course,  also  occur  a 
fairly  appreciable  degree  of  uninterestedness,  which,  however,  may  be  much 
benefited  by  operation  (confer  case  Si.,  Observation  XXXIV).  Now  and 
then  there  develop  also  more  or  less  pronounced  psychoses.  Finally  it  should 
be  mentioned  that  also  hypophysoprivic  dogs  show  characteristic  psychic 
alterations. 

The  pathologico-anatomical  findings  that  are  found  in  this  syndrome  are 
extremely  manifold.  First  of  all,  there  are  tumors  of  the  hypophysis  itself; 
a  detailed  summary  of  the  tumors  of  the  hypophysis  without  acromegaly 
is  found  in  the  publications  of  v.  Kollarits  and  of  v.  Frankl-Hochwart. 

V.  Frankl-Hochwart  has  collected  ninety-seven  cases  of  tumors  of  the 


312  THE    DISEASES    OF    THE    HYPOPHYSIS 

hypophysis  (without  acromegaly).  Among  these  are  twelve  carcinomata, 
thirteen  adenomata/  nine  strumas,  and  twenty-seven  sarcomata.  Among 
the  carcinomata  are  especially  worthy  of  mention  the  hypophysial  duct  flat- 
celled  epithelial  carcinomata.  described  by  Erdheim.  These  proceed  from 
the  accumulations  of  pavement  epithelium,  w^hich  lie  in  the  process  of  the 
glandular  anterior  lobe  that  extends  into  the  hypophysial  peduncle,  and 
which  constitutes  remnants  of  the  hypophysial  duct  cut  off  from  the  oral 
ectoderm.  (See  Figs.  30  and  32.)  Histologically  they  consist  in  epitheKal 
nests  and  concentric  layers  lying  very  close  to  each  other.  Erdheim  compares 
them  with  adamantinomata,  which  also  originate  from  cut-off  parts  of  the  oral 
epithelium,  as  the  remnants  of  the  rudiments  of  the  teeth.  It  may  be  readily 
understood  that  tumors  of  the  hypophysial  duct  mostly  lead  hrst  to  a  dilata- 
tion of  the  sellar  introitus.  Then  the  glandular  hypophysis  microscopically 
may  appear  normal,  as  in  case  of  Bregmann  and  Stein liaus. 

Further,  there  were  to  be  observed,  according  to  v.  Frankl-Hochicart, 
fifteen  cysts,  among  them  the  interesting  case  K.  L.,  that  was  operated  on  by 
V.  Eiselsberg,  and  that  was  more  accurately  described  by  Bychowski.  Finally 
a  vascular  tumor  of  indefinite  texture,  three  gliomata,  two  teratomata, 
seven  tubercles,  three  gummas,  and  one  case  each  of  steatoma,  chondroma 
and  fibroma. 

A  case  that  is  very  important  for  the  pathogenesis  of  hypophysial  dys- 
trophy was  that  of  a  cyst  of  the  hypophysis  recently  reported  by  Mar  anon. 
It  occurred  in  a  man  about  forty  years  old  with  typical  dystrophy.  Micro- 
scopically the  hypophysis  was  apparently  normal,  and  on  microscopical 
examination  more  than  three-fourths  of  the  glandular  part  was  found  to  be 
destroyed  by  an  old  focus  of  hemorrhage. 

I  report  another  case  that  I  observed  a  short  time  ago: 

Observation  XLV . — G.  J.,  fifty-five  years  old,  tailoi.  Entered  the  clinic  'May  30,  191 2. 
Part  of  the  history  was  furnished  by  the  wife.  Until  ten  years  ago  entirely  normal.  Then 
marked  pains  in  the  frontal  region,  attacks  of  vertigo  and  vomiting.  These  pulled  him  down 
very  much,  and  the  attacks  w'ere  attended  with  high  fever.  He  was  confined  to  his  bed 
for  six  months,  then  he  could  again  take  up  his  occupation,  but  since  that  time  his  libido 
has  been  markedly  weakened,  and  finally  disappeared  altogether.  Also  complete  impotence 
came  on.  The  axillary  hairs  gradually  fell  out.  Since  that  time  attacks  of  vertigo  have 
been  less  frequent.  In  the  course  of  the  year  1910  there  gradually  developed  a  swelling  of 
the  thyroid  and  slight  hoarseness.  Otherwise  there  were  no  other  complaints.  Dec, 
191 1,  influenza.  Remained  in  bed  for  six  to  seven  w-eeks,  after  which  there  were  lightning- 
like pains  and  formications  in  the  [lower]  legs.  Also  the  bones  were  tender.  Five  weeks 
ago,  according  to  statement,  suddenly  a  toxic  spasm  in  the  right  hand  and  then  also  in  the 
left  hand. 

Markedly  emaciated  cachectic  individual.  Skin  pale,  dry,  scaly,  the  visible  mucous 
membranes  pale.  Patient  often  cannot  recollect  well,  right  pupil  wider  than  the  left. 
Reaction  somewhat  sluggish.     Eye-grounds  normal.     The  middle  lobe  of  the  thyroid 

^  I  have  already  mentioned  that  not  every  adenoma  must  have  an  increased  function  and  lead 
to  acromegal}'. 


HYPOPHYSIAL   DYSTROPHY  313 

gland  is  of  the  size  of  an  apple,  rather  hard,  and  extends  under  the  sternum,  as  is  seen  on 
examination  of  the  X-ray  plate.  Circumference  of  the  neck  443.^  cm.  Voice  slightly 
roughened.     Chvostek  I  positive.     Electric  excitability  normal. 

Blood-pressure  (according  to  Gartner)  90 

Blood  count:  Erythrocytes,  4,800,000 
Hemoglobin  (Sahli),  57  per  cent. 
Leucocytes,  15,000,  of  which: 
Polymorphonuclear  neutrophiles,  62  per  cent. 
Lymphocytes,  19  per  cent. 
Large  mononuclears,  10  per  cent. 
Eosinophiles,  9  per  cent. 

Pirquet's  reaction  negative.  Patellar  reflexes  weak.  Hyperesthesia  of  both  lower 
extremities.  Nerve  trunks  slightly  tender.  Especial  hyperesthesia  of  the  soles  of  the 
feet.  No  hairs  in  the  axillae.  No  mustache  hairs.  Beard  hairs  almost  entirely  absent. 
Hair  on  the  body  absent  with  the  exception  of  the  pubic  hair  that  is  still  present  somewhat 
copiously.  There  are  no  hairs  at  all  on  the  perineum.  The  entire  body  is  extremely  thin, 
and  there  is  a  cushion  of  fat  still  indicated  only  on  the  mons  Veneris.  The  penis  is  strikingly 
small,  prostate  hardly  palpable.     Nipples  quite  stunted. 

X-ray  examination  of  the  skuU  showed  considerable  enlargement  of  the  sella  turcica  to 
the  size  of  a  two-crown  piece.     Sellar  introitus  apparently  intact. 

Alimentary  glycosuria  (200  gm.  dextrose),  negative. 

Sugar  in  blood,  0.081  per  cent. 

Rapidly  increasing  cachexia,  development  of  a  pneumonia  that  led  to  an  increase  of 
temperature.  Kernig's  symptom  is  positive,  lumbar  puncture  negative.  On  July  5, 
the  blood  count  was: 

Erythrocytes,  3,300,000 

Hemoglobin  (according  to  Sahli),  45  per  cent. 

Leucocytes,  13,900,  of  which: 

Neutrophiles,  58  per  cent. 

Lymphocytes  and  large  mononuclears,  17  per  cent. 

Eosinophiles,  25  per  cent. 

On  both  sides  the  struma  decreases  very  much  in  size,  so  that  on  July  i  the  circumference 
of  the  throat  was  only  39  cm. 

Death  on  July  23. 

Autopsy  {Assistant  Erdheim):  Hazelnut-sized  cyst  of  the  hypophysis  with  marked 
pressure  atrophy  of  the  pituitary  parenchyma  and  dilatation  of  the  sella  turcica.  The 
peduncle  of  the  hypophysis  and  the  base  of  the  skull  unaltered.  The  operculum  sellce 
deeply  retracted.  Cerebral  hernias  with  erosion  of  the  vitreous  table  in  the  domains  of 
{he  posterior  and  middle  cerebral  fossae.  But  the  convolutions  are  not  flattened.  Grow- 
ing struma  (Langhans)  proceeding  from  the  middle  lobe  of  the  thyroid  gland  with  exten- 
sive pressure  atrophy  of  the  thyroid  parenchyma  proper.  The  thymus  small,  rich  in  fat, 
the  suprarenal  markedly  atrophic,  the  atrophy  affecting  exclusively  the  cortex,  the  medulla 
remaining  abimdantly  developed.  Atrophy  of  the  testicles,  marked  general  marasmus, 
marked  senile  atrophy  of  the  upper  and  lower  jaws  without  almost  complete  absence  of 
teeth.     Lobular  pneumonia,  etc. 

The  microscopical  examination  of  the  hypophysis  in  the  sagittal  direction,  for  which  I 
am  indebted  to  Dr.  Erdheim,  shows  the  following:  The  hypophysis  is  taken  up  centrally 
by  a  single-chambered,  smooth-walled  cyst,  which  is  partly  filled  with  a  homogeneous 
portion  and  partly  with  a  shreddy  portion.  The  cyst  for  the  most  part  is  not  hned 
with  epithelium,  there  being  present  a  single  layer  of  epithelial  cells  for  a  short  distance 


314  THE    DISEASES    OF    THE    HYPOPHYSIS 

onl}-.  The  tissue  surrounding  the  cyst  is  l-i  mm.  thick  and  constitutes  the  markedly 
pressure  atrophied,  strongly  fibrous,  glandular  tissue  of  the  hypophysis.  This  is  bounded 
externally  bj-  the  fibrous  capsule  of  the  hj-pophj'sis. 

The  microscopical  examination  of  a  piece  of  the  thyroid  gland  showed  a  well-limited 
benign  epithelial  tumor  with  numerous  cavities  filled  with  colloid,  that  are  separated  from 
each  other  by  septa  that  are  purely  epithelial. 

In  this  case  there  is  surely  a  marked  retrenchment  of  function  of  the 
hypophysis  of  ten  years'  standing  with  a  gradual  increasing  cachexia.  The 
disease  was  ushered  in  ^^^th  an  unknown  infectious  process.  Perhaps  this 
also  affected  the  hypophysis  and  gave  occasion  for  the  cyst  formation.  At 
all  events  we  find  since  that  time  a  disturbance  of  the  generative  function,  a 
gradual  partial  retrogression  of  the  secondary  sexual  characters,  sHght 
atrophy  of  the  accessory  genital  apparatus,  especially  the  prostate.  Perhaps 
the  marked  atrophy  of  the  suprarenal  cortex  plays  a  part  in  the  retrogression 
of  the  genitals  and  of  the  secondary  sexual  characters. 

Worthy  of  mention  in  this  case  is  also  the  uncommonly  rapid  diminution 
of  the  struma.  At  the  beginning  this  was  so  hard  that  originally  we  thought 
of  a  malignant  process. 

Much  cited  is  the  case  of  Madeliing.  This  concerned  a  nine-year-old  girl. 
At  the  age  of  six  years,  a  shot  injury  from  a  Flobert  gun.  The  girl  has  re- 
mained behind  in  mental  development,  is  very  quiet.  Considerable  adiposity 
which  first  developed  after  the  injury  fat  the  time  the  patient  remained  in 
bed  for  five  months) .  The  shot  had  penetrated  the  sella  turcica  via  the  left 
eye;  there  was  a  slight  dragging  of  the  left  leg  and  weakness  of  the  left 
arm. 

Besides  these  tumors  originating  from  the  h}-pophysis  there  are  numerous 
processes  in  the  neighborhood  of  the  h}'pophysis  in  which  such  cases  of 
dystrophia  adiposo-genitalis  are  found.  To  these  belong  tumors  that  pro- 
ceed from  the  brain  membranes  or  the  bones,  or  brain  tumors.  All  possible 
brain  processes  can  lead  to  genital  disturbances  and  adiposity,  in  so  far  as  they 
apparently  call  forth  an  increase  of  pressure  in  the  third  ventricle.  Already 
in  1855,  Fr.  Konig  reported  a  case  that  seems  to  me  to  belong  in  this  category. 
It  was  that  of  an  eighteen-year-old  girl  with  undeveloped  genitalia;  she 
had  never  menstruated.  The  visual  power  was  disturbed.  The  head  was 
very  large.  Here  was  found  a  hydrops  of  all  ventricles  and  atrophy  of 
the  optic  nerves;  in  the  cerebellum,  on  the  left,  an  echinococcus.  This  case, 
on  account  of  the  deficient  ossification  of  the  pelvis  was  considered  by  A. 
Paltauf  one  of  the  true  dwarfism.  For  the  first  exact  description  of  such 
cases  we  have  to  thank  E.  Midler;  but  Axenfeld,  already  in  1903,  had  pointed 
out  that  tumors  at  the  base  of  the  brain  may  produce  permanent  amenorrhea 
even  at  the  beginning  of  the  disease.  In  many  of  E.  Mullers  cases  there 
developed  a  pronounced  obesity.  There  was  observed  in  the  two  autopsied 
cases  a  tumor  of  the  cerebellum,  and  a  tumor  of  the  occipital  lobe  respect- 


HYPOPHYSIAL   DYSTROPHY  315 

ively.  In  the  cases  that  he  observed  only  chnically  there  was  probably  sec- 
ondary ventricular  hydrops  after  brain  tumors. 

Marinesco  and  Goldstein  described  two  cases  of  hydrocephalus  with  genital 
hypoplasia  and  obesity  (no  autopsy).  Like  the  case  of  E.  MuUer,  the  patients 
were  small  of  stature.  Neurath  further  reports  cases  of  hydrocephalus  with 
obesity  in  children.  The  genital  disturbance  was  not  always  distinct.  We 
have  to  consider  however  that  in  children  the  genital  disturbance  would  not 
be  so  prominent  as  in  adolescents.  In  a  review  of  the  pertinent  literature 
I  have  received  the  impression  that  in  the  slight  grades  of  hypophysial 
insufhciency  the  first  sign  is  the  development  of  an  obesity. 

Also  case  2  and  case  3  of  Babonneix  and  Paisseau  belong  to  the  group 
just  mentioned.  In  case  2  as  in  case  i  of  Neurath  the  hydrocephalus  de- 
veloped after  scarlet  fever. 

Pathogenesis. — The  views  as  to  the  pathogenesis  of  the  clinical  picture 
described,  or  as  to  the  role  that  the  hypophysis  plays  in  it,  deviate  from  one 
another  markedly.  Even  although  at  the  present  we  are  not  in  the  position 
to  clarify  satisfactorily  all  the  manifestations  belonging  to  this  picture,  I 
still  believe  that  the  later  results  of  pathological  physiology  and  the  evident 
analogies  with  those  diseases  of  the  thyroid  that  are  well-known  have  fur- 
nished us  with  a  valuable  criterion.  Let  us  first  consider  the  results  of  the 
pathological  physiology.  The  difficult  accessibility  of  the  organ  and  its 
immediate  vicinity  to  centers  important  for  life  have  made  extraordinarily 
difficult  the  experimental  studies  of  the  symptoms  dependent  on  loss  of  the 
hypophysial  apparatus.  Only  recent  years  have  brought  comparative  clear- 
ness to  the  solution  of  the  problem.  In  stating  the  experiments  and  their 
results  I  shall  confine  myself  to  the  most  important.  Paulesco  was  the  first  to 
succeed  in  the  complete  extirpation  of  the  whole  hypophysial  apparatus. 
He  and  Gushing  used  the  method  of  trepanation  and  pushing  aside  the 
cerebral  hemispheres.  Both  authors  came  to  the  result  that  the  complete 
extirpation  of  the  entire  hypophysial  apparatus  in  dogs  leads  to  death  under 
fall  of  temperature  and  blood-pressure,  slowing  of  the  pulse,  increasing 
apathy,  and  deep  coma,  and  they  inferred  that  the  hypophysis  is  an  organ 
important  for  life,  of  which  the  anterior  lobe  is  the  part  important  for  life; 
this  because  complete  extirpation  of  this  alone  led  to  all  the  manifestations 
described.  According  to  Gushing  total  extirpation  of  the  posterior  lobe 
in  several  cases  called  forth  convulsions  and  sexual  overexcitement,  but 
mostly  was  without  especial  action.  On  the  contrary  B.  Aschner  on  the  basis 
of  his  very  beautiful  experiments  upheld  the  opinion  that  the  lethal  result 
described  depends  on  an  injury  to  the  tuber  cinereum.  Aschner  used  the 
buccal  method  and  found  lethal  coma  on  injury  to  the  tuber  cinereum  and 
opening  of  the  third  ventricle.  Less  severe  injuries  or  wound  infection  brings 
about  the  appearance  of  the  so-called  hypophysoprivic  cachexia  (marked 
fall  of  temperature,  apathy,  anorexia,  polyuria,  eventually  glycosuria,  also 


3l6  THE    DISEASES    OF    THE    HYPOPHYSIS 

adynamia,  crying-out  of  the  animals  under  experimentation,  tonic  and  clonic 
convulsions  and  death).  On  the  contrary  when  the  hypophysis  is  removed 
without  injury  to  the  hypophysial  peduncle,  the  manifestations  detailed  re- 
main absent,  the  animals  are  again  lively  a  few  hours  after  the  operation,  and 
remain  alive.  There  develops,  especially  in  youthful  animals  a  condition 
that  in  the  most  important  features  simulates  hypophysial  dystrophia 
adiposo-genitalis.  The  animals  become  fat,  they  remain  appreciably  be- 
hind in  development,  the  dentition  and  the  ossification  are  markedly  delayed, 
the  epiphysial  junctures  can  remain  open  for  a  long  while,  the  childish 
proportions  are  retained,  and  the  epidermoidal  structures,  such  as  the 
hairs  and  claws,  show  developmental  disturbances.  The  genitalia  remain 
markedly  infantile,  spermatogenesis  is  extremely  sparse,  the  sexual  instinct 
is  markedly  reduced,  in  female  animals  rut  is  weakened  and  never  is  there 
pregnancy.  Investigations  as  to  the  metabolism  of  such  animals  shows  that 
there  is  great  similarity  with  alterations  that  Eppinger,  Rudinger,  and  / 
found  in  animals  without  thyroids.  The  fasting  protein  exchange  is 
markedly  reduced.  The  glycosuric  action  .of  adrenalin  is  reduced,  and  is 
associated  with  a  slowing  of  the  pulse  and  of  breathing,  reduction  of  the 
body  temperature,  and  an  appreciable  reduction  of  caloric  production. 
Benedict  and  Honians  have  demonstrated  the  reduction  in  the  carbonic  acid 
production,  Aschner  and  Forges  the  reduction  of  oxygen  consumption,  in 
such  animals.  The  alterations  described  must  be  referred  to  the  extirpation 
of  the  glandular  hypophysis,  as  extirpation  of  the  posterior  lobe  alone  calls 
forth  no  essential  alteration.  The  traces  of  the  epithelial  seam  of  the  inter- 
media that  must  remain  behind  in  the  hypophysial  peduncle  do  not,  as 
Aschner  supposes,  come  into  consideration. 

It  is  perhaps  hardly  necessary  to  describe  in  detail  the  great  similarity 
of  this  symptom  complex  produced  by  extirpation  of  the  hypophysial  appa- 
ratus with  that  of  hypophysial  dystrophy.  In  spite  of  this  I  must  enter 
into  a  discussion  of  the  individual  symptoms  and  their  relation  to  the  hy- 
pophysis, as  just  on  this  point  the  opinions  differ  from  each  other  consider- 
ably. In  this  discussion  we  shall  have  to  keep  our  attention  directed  to  the 
fact  that,  as  in  acromegaly,  the  cardinal  symptoms  due  to  the  deficiency  of 
function  of  the  hypophysis  (in  acromegaly,  the  excess  of  hypophysis  function) 
must  be  kept  separated  from  the  symptoms  that  are  due  to  the  pressure  of 
the  growing  tumor  on  the  neighboring  organs  or  due  to  the  associated  disease 
of  other  ductless  glands. 

To-day  the  view  of  most  authors  is  that  hypophysial  dystrophy  with 
both  of  these  cardinal  symptoms — the  genital  disturbances  and  the  obesity — 
depends  on  a  loss  or  diminution  of  function  of  the  hypophysis  (v.  Xoorden, 
Fettsucht  [Obesity]  2nd  edition).  The  relation  of  both  these  symptoms  to 
the  hypophysis  has,  however,  been  called  into  question.  Erdheim  assumed 
that  the  tumor  on  growing  out  from  the  sella  actuated  an  as  yet  unknown 


HYPOPHYSIAL  DYSTROPHY  317 

center  at  the  base  of  the  brain,  occasioning  obesity.  Erdheim  was  forced  to 
this  conception  by  the  observations  that  also  tumors  situated  extrasellarly 
can  lead  to  obesity.  Among  those  authors  who  refer  the  obesity  directly  to 
the  loss  of  function  the  hypophysis,  there  are  some  who  refer  the  tumor  to  the 
loss  of  function  of  the  nervous  lobe,  others  to  that  of  the  glandular.  Espe- 
cially B.  Fischer  is  an  adherent  to  the  doctrine  that  it  is  due  to  the  nervous 
lobe.  He  states  as  a  chief  argument  the  fact  that  the  genital  disturbance 
belongs  to  the  early  symptoms  of  acromegaly  too.  Here  it  is  produced  by 
pressure  on  the  nervous  lobe.  Also  Gushing,  who  formerly  in  common  with 
Crowe  and  Romans,  brought  the  obesity  into  relation  with  the  glandular 
hypophysis,  now  agrees  with  Goetsch  and  Jacobson  as  to  the  significance  of 
the  posterior  lobe.  Finally,  another  much  discussed  question  is  as  to  whether 
the  obesity  is  produced  directly  by  the  alteration  of  function  of  the  hypo- 
physis or  secondarily  by  the  functional  disturbance  of  the  sexual  glands. 
Lately  B.  Aschner  has  again  taken  up  Erdheim's  hypophysis  and  has  cham- 
pioned an  atrophic  center  at  the  base  of  the  brain,  the  function  of  which  is  dis- 
turbed by  the  pressure  of  the  growing  tumor.  He  bases  his  opinion  on  the 
fact  that  in  growing  animals  total  extirpation  of  the  hypophysis  never  leads 
to  a  marked  grade  of  obesity,  nor  to  such  distinctly  pronounced  genital 
disturbances  as  in  youthful  human  beings.  The  result  of  the  operation^ 
on  tumors  of  the  hypophysis  in  human  beings,  so  far  as  concerns  the  les- 
sening of  the  obesity  and  the  improvement  of  the  genital  function,  depends 
on  a  release  of  pressure  from  the  hypothalamic  region.  Aschner  sees  an 
especially  strong  support  for  his  opinion  in  the  experiments,  the  results  of 
which  were  recently  pubhshed,  through  which  it  was  possible  to  produce 
marked  trophic  disturbance  of  the  sexual  glands  through  injury  to  the  hypo- 
thalamic region.  To  this  view,  E.  Muller  has  already  opposed  the  fact  that 
trophic  disturbances  in  processes  at  the  base  of  the  skull  must  be  ascribed  to 
the  compression  of  the  hypophysis,  as  dystrophy  and  sexual  glandular 
disturbances  are  absent  in  brain  tumors  unattended  with  hydrocephalus 
that  have  not  involved  the  hypophysis.  Also  Marinesco  and  Goldstein 
incline  to  this  opinion,  v.  Noorden  regards  the  obesity  as  thyrogenic  (through 
secondary  influencing  of  the  function  of  the  thyroid  gland) .  Finally,  here, 
as  in  acromegaly,  the  attempt  has  been  made  to  place  in  the  foreground 
a  primary  disturbance  of  the  sexual  glands  {Schuller,  Tandler  and  Grosz) . 
Novak,  on  the  other  hand,  influenced  by  the  fact  that  operation  may  bring 
about  an  improvement  of  the  genital  function  without  essential  effect  on 
the  obesity,  is  of  the  opinion  that  the  obesity  is  independent  of  the  genital 
disturbance.     We  see  almost  "quot  capita,  tot  sententiae." 

I  shall  first  describe  the  genital  disturbance,  as  I  am  of  the  opinion  that 
the  obesity  is  given  its  characteristic  expression  through  the  genital  disturb- 
ance. It  must  here  again  be  mentioned  that  the  genital  disturbance  in  hypo- 
physial dystrophy  is  throughout  not  identical  with  that  of  acromegaly,  as 


3l8  THE    DISEASES    Of    THE    HYPOPHYSIS 

was  formerly  assumed  to  be  the  case,  and  which  has  recently  again  been  up- 
held by  B.  Fischer,  Cushing  and  very  recently  also  by  Biedl.  We  find  on  the 
contrary  that  the  beginning  of  acromegaly  the  genital  disturbance  is  exactly 
the  opposite  from  what  it  is  in  h>'pophysial  dystrophy,  and  also  varies  from  it 
later  on  in  the  disease.  In  acromegaly  is  found  at  first  even  increase  of  the 
generative  function,  at  all  events  always  a  marked  accentuation  of  the  func- 
tion of  the  interstitial  glands  or  at  least  no  signs  of  a  disturbance.  Apart 
from  rare  exceptions,  that  are  becoming  even  fewer,  the  condition  lasts  until 
well  in  the  course  of  the  disease.  On  the  contrary  we  find  in  hypophysial 
dystrophy  from  the  beginning,  in  addition  to  the  disturbance  in  the  function 
of  the  generative  glands,  disturbances  of  the  interstitial  glands.  This  is  the 
more  pronounced  the  younger  the  individual  aft'ected.  Moreover,  the  cases 
in  which  the  disease  begins  in  later  life  are  very  rare.  In  them  the  dis- 
turbance of  the  generative  function  is  more  distinct  than  that  of  the  interstitial 
glands,  indeed  it  appears  as  though  the  retrogression  of  the  once  fully  devel- 
oped secondary  sexual  characters  only  becomes  more  distinct  when  atrophic 
processes  in  the  other  ductless  glands,  especially  the  suprarenal  cortex,  are 
added,  as  happened  in  the  case  I  reported  (Observation  XLV).  Here  indeed 
may  occur  all  transitions  to  multiple  ductless  glandular  sclerosis  with  its  pro- 
nounced late  eunuchoidism.  Aschner  mentions  that  the  disturbances  of  the 
function  of  the  sexual  glands  in  animals  experimented  on  are  found  wholly 
pronounced  only  when  the  extirpation  of  the  hypophysis  has  been  undertaken 
in  an  animal  that  is  still  developing.  It  seems  to  me  that  this  does  not  con- 
stitute a  contradiction  to,  but  rather  an  agreement  \\\i\\.  the  experiences  met 
with  in  human  pathology. 

Clinical  experience  further  teaches  us  that  in  hypophysial  dystrophy  the 
genital  disturbances  may  develop  fully  even  if  the  pathological  process  is 
limited  to  the  h^-pophysis  and  entirely  intrasellar.  I  refer  to  the  case  of 
Maranon  or  to  Observation  XLV.  If  for  the  existence  of  the  genital  disturb- 
ance there  was  necessary  a  pressure  on  a  center  lying  in  the  hypothalamic 
region,  therefore  a  forward  growth  of  the  tumor,  in  these  cases  the  occurrence 
of  the  genital  disturbance  would  be  as  inexplicable  as  in  animal  experimenta- 
tion after  extirpation  of  the  hypophysis.  Also  in  many  cases  of  acromegaly 
in  which  the  sellar  introitus  is  dilated,  in  which  growing  out  of  the  tumor 
leads  to  visual  disturbances,  perhaps  early,  and  in  which  there  are  manifesta- 
tions of  an  increased  brain  pressure,  we  would  then  find  genital  disturbances 
of  the  type  of  hypophysial  dystrophy.  From  all  this  seems  to  me  to  be 
elicited  the  fact  that  loss  of  function  of  the  hypophysial  function  alone  can 
lead  to  gential  disturbances  of  the  type  of  hypophysial  dystrophy,  just  as 
conditions  of  hyperfunction  of  the  hypophysis  may  lead  to  those  of  the  acro- 
megalic type.  The  results  of  the  operative  treatment  of  hypophysial  dys- 
trophy throughout — as  I  already  mentioned  in  1908 — do  not  speak  against 
this  supposition.     The  most  essential  result  consists  in  the  relief  of  the  head- 


HYPOPHYSIAL   DYSTROPHY  319 

aches  and  an  improvement  in  the  visual  power  and  manifestations  that  are 
intelligible  as  the  result  of  the  release  of  pressure.  In  some  cases  are  also 
observed  the  occurrence  of  slight  menstrual  hemorrhages  or  of  erections. 
As  far  as  I  know,  this  improvement  in  the  activity  of  the  sexual  glands  is 
only  slight,  and  may  also  be  explained  by  the  release  of  the  pressure  from  the 
part  of  the  hypophysis  that  is  still  capable  of  functionating. 

I  must  naturally  leave  open  the  question  of  the  possibility  that  through 
damaging  of  centers  in  the  hypothalamic  region  similar  disturbances  may  be 
brought  about  in  genital  function,  and  that  in  the  cases  of  diseases  of  the 
mid-brain  which  lead  to  hypophysial  dystrophy,  without  any  essential  patho- 
logico-anatomical  alterations  of  the  hypophysis,  the  disturbance  may  per- 
haps find  its  explanation  in  the  fact — and  indeed  even  in  such  cases  does  the 
position  seem  to  me  just  as  capable  of  being  maintained  in  discussion  as  in 
the  cases  mentioned  above — that  through  such  processes  the  function  of  the 
hypophysis  is  disturbed  on  account  of  the  characteristic  topographic  rela- 
tions, the  more  so  because  in  such  cases  we  tend  to  find  also  other  symptoms 
of  hypophysial  dystrophy,  symptoms  such  as  disturbance  in  growth,  raising  of 
the  limit  of  assimilation  of  carbohydrates,  alterations  of  the  blood  picture,  etc. 

Let  us  now  consider  the  obesity.  The  obesity  to  be  observed  in  cases  of 
hypophysial  tumors  without  acromegaly  shows  in  respect  to  the  distribution 
of  fat  full  analogies  with  that  which  is  seen  in  eunuchs  and  eunuchoids. 
{v.  Noorden).  Especially  important  seems  to  me  the  circumstance  that  even 
where  there  is  no  obesity  proper  the  abnormal  distribution  of  fat  is  always 
indicated.  This  holds  true  almost  always,  even  in  markedly  cachectic 
emaciated  individuals.  Moreover,  we  hardly  find  this  distribution  of  fat 
expressed  in  typical  manner  unless  there  is  present  at  least  some  degree  of 
insufficiency.  Finally  I  would  again  point  out  that  in  the  predominating 
majority  of  the  observations  reported  up  to  the  present  the  beginning  of  the 
disease  occurred  in  youth.  Among  the  cases  that  have  developed  the  dis- 
ease later  are  apparently  those  in  which  the  abnormal  distribution  of  fat  is 
indeed  indicated,  but  in  whom  there  is  otherwise  no  obesity,  but  marked 
emaciation  rather. 

The  loss  of  the  function  of  the  hypophysis  hence  seems  to  lead  to  obesity 
only  under  certain  conditions.  Marked  cachexia  may  prevent  the  occurrence 
of  the  obesity,  apart  from  the  suggestion  of  the  abnormal  distribution  of  fat. 
As  example,  I  quote  the  above  accurately  reported  Observation  XLV,  or 
the  case  of  Sokolof  in  which  a  large  gumma  was  found  in  the  hypophysis. 
For  the  most  part  this  seems  to  be  the  case  in  sclerotic  processes  that  involve 
not  only  the  hypophysis,  but  also  other  ductless  glands.  In  multiple  duct- 
less glandular  sclerosis,  we  come  to  recognize  the  rapidly  developing  cachexia 
as  an  important  symptom;  here  is  found  at  most  a  suggestion  of  the  abnormal 
distribution  of  fat,  or  no  obesity,  even  when  the  hypophysis  is  seriously  in- 
volved (see  Chapter  XI). 


320  THE    DISEASES    OF    THE    HYPOPHYSIS 

If  we  assume,  as  does  Aschner,  in  agreement  with  Erdheim's  hypothesis, 
that  the  higher  grades  of  obesity  only  come  about  through  the  pressure  of  the 
superiorly  growing  tumor  on  a  center  lying  in  the  hypothalamic  region,  the 
occurrence  of  these  in  cases  in  which  the  process  is  limited  to  the  sella  would 
be  unintelligible.  We  would  therefore  find  obesity  likewise  in  those  cases  of 
acromegaly  in  which  the  tumor  grows  out  of  the  sella  and  leads  to  marked 
eye  disturbance.  In  these  diseases,  however,  obesity  belongs  to  the  rarities, 
and  is  even  then  apparently  not  of  a  high  grade.  Finally,  as  is  even  of  more 
weight,  we  never  find  in  typical  acromegaly  an  indication  of  eunuchoid  fat 
distribution,  such  as  we  always  find  in  the  dystrophy.  Hence  it  seems  to  me, 
that  the  obesity  depends  entirely  on  the  genital  disturbance  and  to  be  a  re- 
sidual manifestation  of  the  same.  Under  circumstances  we  also  find  in  pure 
eunuchoidism  an  obesity  of  quite  the  same  type  as  in  hypophysial  dystrophy; 
the  same  distribution  of  fat  and  in  addition  the  same  softness  and  delicacy  of 
the  skin;  here,  however,  there  can  be  no  question  that  there  is  no  process  in 
the  hypothalamic  region. 

Also  the  remaining  cardinal  symptoms  speak  for  the  supposition  that  the 
clinical  picture  depends  on  a  loss  or  decrease  of  function  of  the  hypophysial 
apparatus.  The  reduction  in  the  exchange  of  gases  fits  in  well  with  the  re- 
sults of  experimental  physiology,  as  does  also  the  reduction  of  the  excitability 
of  the  vegetative  nerves  observed  in  my  cases,  and  also  the  sluggishness  of  carbo- 
hydrate metabolism.  The  supposition  of  Aschner  as  to  the  genesis  of  glyco- 
suria in  acromegaly  is  made  quite  unlikely  by  the  fact  that  then  we  would 
have  to  expect  glycosuria  very  much  more  frequently  in  intrasellar  or 
extrasellar  tumors  without  acromegaly  than  in  acromegaly,  while  as  already 
mentioned  the  carbohydrate  metabolism  shows  in  all  cases  the  abnormal 
sluggishness.  The  case  of  Link,  with  tumor  of  the  hypophysis  (without 
acromegaly)  and  diabetes,  does  not  mean  anything.  An  occasional  individ- 
ual may  have  degeneration  of  the  insular  apparatus  and  diabetes  and  also  a 
tumor  of  the  hypophysis. 

Finally  the  growth  disturbance!  On  a  careful  review  of  the  hterature,  I  have 
been  able  to  ascertain  that  all  cases  that  begin  in  youth  are  associated  with  a 
disturbance  of  growth,  so  that  in  this  respect  there  is  an  entire  agreement 
\yiih  experimental  pathology.  I  cannot  agree  with  the  conjecture  of  Aschner 
that  true  dwarfism  depends  on  a  lessening  of  the  function  of  the  hypophysial 
apparatus  (see  Chapter  XII). 

On  taking  into  consideration  all  the  facts  and  convictions  set  forth  above 
it  is  my  opinion  that  to-day  we  are  justified  in  the  assertion  that  the  disease 
picture  of  hypophysial  dystrophy  depends  on  a  loss  or  lessening  of  the  function 
of  the  hypophysial  apparatus. 

Finally  the  question  comes  up  for  discussion  as  to  which  part  of  the 
h3'pophysial  dystrophy  is  to  be  ascribed  to  the  involvement  of  the  glandular 
lobe  of  the  hypophysis  and  which  part  to  that  of  the  nervous  lobe.     B.  Fischer 


HYPOPHYSIAL    DYSTROPHY  32 1 

has  upheld  the  opinion  that  the  obesity  and  the  genital  disturbances  are  due  to 
the  involvement  of  the  nervous  lobe;  Cushing  has  agreed  with  him  and  would 
ascribe  to  the  glandular  lobe  only  the  growth  disturbance.  Fischer  regards 
as  the  principal  support  of  his  argument  the  similarity  of  the  kind  of  genital 
disturbance  in  acromegaly  and  hypophysial  dystrophy.  I  need  hardly  again 
mention  that  this  is  not  correct.  A  further  support  for  the  view  is  found  in 
the  known  tonic  actions  of  the  extracts  of  the  posterior  lobe  on  the  genitalia, 
and  further  the  circumstance  that  in  certain  typical  cases  of  hypophysial  dys- 
trophy, especially  in  squamous  epithelial  carcinoma,  the  sellar  introitus  is  very 
much  distended  and  the  nervous  lobe  is  found  to  be  destroyed,  while  the 
glandular  part  is  well  retained  (for  example,  case  2  of  Bregman  and  Steinhaus) , 
although  we  find  a  very  much  larger  number  of  cases  in  which  the  glandular 
hypophysis  has  been  destroyed  by  cyst  formation,  gummas,  etc.,  while  the 
nervous  lobe  was  found  to  be  intact.  The  known  tonic  action  of  the  extracts 
of  the  posterior  lobe  applies  only,  as  before  mentioned,  to  the  nerves  of  the 
uterus,  and  on  the  contrary  an  activating  influence  on  the  sexual  glands  is  not 
at  all  known.  Against  a  direct  connection  of  a  disturbance  of  the  function  of 
the  posterior  lobe  with  the  genital  disturbance  speaks,  however,  the  following: 
It  is  very  probable  that  the  polyurias  of  longer  or  shorter  duration  that  occur 
so  frequently  depend  on  an  irritation  of  the  posterior  lobe.  Now  such  poly- 
urias of  long  duration  are  found  also  in  cases  with  pronounced  genital  disturb- 
ance. If,  therefore,  we  refer  the  polyuria  to  a  hyperfunction  and  the  genital 
disturbance  to  a  falling  away  of  the  function  of  the  posterior  lobe,  we  would 
not  expect  to  find  them  both  occurring  together.  In  addition  polyuria  is 
found  eventually  in  acromegaly,  also  in  cases  with  increased  function  of  the 
genitalia,  or  at  least  with  failure  of  a  functional  disturbance  of  the  interstitial 
glands,  hence  it  is  quite  independent  of  the  nature  of  the  genital  disturbance. 

I  must  consider  the  question  of  polyuria  somewhat  more  intimately. 
Let  us  remember  that  transitory  or  more  permanent  polyurias,  that  eventu- 
ally may  show  the  entire  disease  picture  of  diabetes  insipidus,  are  found  very 
frequently  in  the  most  diverse  hypophysial  diseases  without  acromegaly, 
and  indeed  sometimes  in  acromegaly,  and  that  the  same  thing  is  observed 
also  in  tumors  and  other  diseases  of  the  brain-stem.  Very  important  facts 
for  the  origin  of  these  polyurias  are  furnished  by  experimental  pathology. 
As  has  been  previously  presented,  there  may  be  obtained  from  the  nervous 
lobe  of  the  hypophysis  an  albumin-free  heat-stabile  extract  that  possesses 
in  addition  to  its  known  action  on  the  blood-pressure,  exquisite  diuretic 
characteristics.  Sclidfer  states  further  that  the  polyuria  occurs  in  the  different 
classes  of  animals  also  after  feeding  with  the  posterior  lobe.  Furthermore, 
implantation  of  the  hypophysis  causes  an  increase  of  the  amount  of  urine 
{Crowe,  Cushing  and  Homans)  that  again  disappears  after  extirpation  of  the 
transplant.     Under  circumstances  the  polyuria  lasts  for  several  days. 

Furthermore,  polyuria  that  may  last  for  many  days  is  very  frequent  in 


322  THE    DISEASES    OF    THE    HYPOPHYSIS 

operations  on  the  hypophyses,  as  all  later  authors  agree  (Schdfer,  dishing 
and  others).  Schdjer  found  a  similar  polyuria  in  nonbloody  mechanical 
or  chemical  irritation  of  the  hypophysis.  All  these  experiments  seem  to 
indicate  that  increased  production  of  this  secretion  through  chronic  condi- 
tions of  irritation  (pressure,  inflammation,  etc.)  can  occasion  a  polyuria. 

On  the  other  hand  it  is  known  that  in  the  medulla  oblongata  and  also 
further  up  in  the  brain-stem,  there  are  found  loci,  the  irritation  of  which 
may  cause  marked  polyuria  lasting  for  days.  As  is  known.  Bernard's  piqure 
is  associated  with  polyuria.  If,  however,  the  puncture  is  done  further  up, 
exclusively,  polyuria  results. 

Hence  the  conditions  are  such  as  the  conditions  with  regard  to  the  genital 
disturbance.  Extirpation  of  the  hypophysis  or  destruction  of  a  place  in  the 
siihthalmic  region  lying  above  the  hypophysis  leads  to  genital  atrophy;  irritation 
oj  the  posterior  lobe  or  irritation  of  a  definite  place  in  the  brain-stem  leads  to 
polyuria. 

Hence  one  can  readily  conceive  that  in  tumors  or  inflammatory  processes 
in  the  brain-stem  or  at  the  base  [of  the  brain],  a  continuing  condition  of  irri- 
tation may  be  set  up  in  these  centers,  and  on  account  of  it  a  transitory  or 
permanent  polyuria. 

The  following  possibilities  should  be  considered:  These  polyurias  may 
be  always  the  result  of  a  condition  of  irritation  or  of  hyperfunction  of  the 
pars  intermedia  or  the  posterior  lobe,  assuming  that  tumors  proceeding 
from  the  glandular  hypophysis  or  from  the  peduncle,  and  other  lesions, 
irritate  the  posterior  lobe  for  a  longer  or  shorter  time,  and  that  disease 
processes  localized  to  the  brain-stem  also  influence  the  hypophysis  in  like 
manner;  or  all  these  polyurias  may  originate  through  irritation  of  the 
nervous  centers  lying  in  the  brain-stem;  or,  finally,  it  is  possible  that  there 
is  a  nervous  connection  between  those  centers  and  the  nervous  posterior  lobe, 
and  that  irritation  of  the  former  spurs  on  the  latter  to  increased  secretion. 
The  decision  of  this  question  is  not  as  yet  possible.  However,  it  seems  to 
me  very  improbable  that  the  exquisite  diuretic  action  of  infundibular  ex- 
tracts stands  in  direct  relation  with  the  polyurias  of  the  tumors  of  the  hypo- 
physis. Also  it  seems  very  probable  that  in  processes  in  the  immediate 
neighborhood  of  the  hypophysial  peduncle,  the  same  series  of  actions  is  in 
play;  naturally  we  must  acknowledge  the  possibility  that  such  polyurias  may 
come  about  through  stimulation  of  centers  in  the  brain-stem,  without  media- 
tion of  the  hypophysis. 

Finally  we  must  consider  the  questions  as  to  whether  there  are  any 
grounds  for  the  fact  that  also  idiopathic  diabetes  insipidus  may  be  referred  to 
an  increase  of  function  of  the  pars  intermedia.  The  question  has  been  re- 
cently discussed  by  Frank,  among  others.  As  up  to  the  present  there  are  no 
pathologico-anatomical  findings  corresponding  to  diabetes  insipidus — and  we 
must  also  not  neglect  to  mention  that  not  enough  attention  has  been  directed 


HYPOPHYSIAL    DYSTROPHY 


323 


to  the  hypophysis  in  this  respect — it  seems  to  be  worth  while  to  approach  the 
question  by  asking  whether  there  exist  any  essential  ditterences  between  the 
pol^nirias  of  idiopathic  and  of  symptomatic  diabetes  insipidus.  Forschbach 
and  Weber  assume  that  in  idiopathic  diabetes  insipidus  the  kidnevs  are 
especially  sensitive  and  irritable,  so  that  they  react  to  a  diet  rich  in  gram 
molecules  [molenreich]  with  more  marked  diuresis.  TaJquist  and  E.  Meyer 
formulate  their  opinion  by  the  assumption  that  the  kidneys  are  incapable 
of  concentrating  the  urine.  Breuning  behcA-es,  from  a  collection  of  the  per- 
tinent cases  from  the  literature,  that  he  is  able  to  conclude  that  (also  in  symp- 
tomatic diabetes  insipidus)  the  kidneys  have  lost  the  capacity  of  concentra- 
tion. Also  Frank  found  it  absent  in  his  case.  I  must  point  out  in  opposition 
to  this  that  this  dictum  in  a  general  sense  does  not  hold  for  svmptomatic 
diabetes  insipidus.  I  refer  to  Observation  XXXA'II.  in  which  the  specific 
gravity  of  the  urine,  after  several  days  of  vomiting,  rapidly  rose  to  1013. 
Also  the  test  in  case  K.  Observation  XXXVIII,  showed,  after  increase  of 
salt  to  the  diet,  an  increase  in  the  ehmination  of  salt,  but  during  this  day 
the  total  amount  of  urine  did  not  increase.  I  would  here  mention  some  ex- 
periments that  we  carried  out  on  rabbits.  In  these  injection  of  pituitrinum 
infundibulare  produces  marked  diuresis.  When  sodium  chloride  is  adminis- 
tered at  the  same  time  there  occurred,  in  spite  of  diuresis,  an  appreciable 
increase  of  the  concentration  of  the  urine.  Hence  it  appears  to  me  that  we 
must  leave  the  question  of  the  genesis  of  idiopathic  diabetes  insipidus  open. 

For  the  comprehension  of  the  diseases  of  the  hypophysis,  a  careful  con- 
sideration of  the  relations  between  the  hypophysis  and  the  thyroid  gland  seems 
indispensable,  so  that  I  shall  here  enter  into  a  more  intimate  discussion  of 
these  relations.  First  some  experimental  facts.  After  extirpation  of  the 
thyroid  gland  in  young  animals  there  has  been  observed  an  enlargement  of 
the  hypophysis  (Gley  and  others).  The  enlargement  affects  the  glandular 
part.  Vacuoles  are  found  in  the  cells.  Conversely,  an  enlargement  of  the 
thyroid  gland  occurs  after  extirpation  of  a  part  of  the  adenoma  in  acromegaly. 
In  myxedema  the  hypophysis  has  been  found  to  be  enlarged;  sometimes, 
not  always.  In  such  cases  the  enlargement  may  well  depend  on  strumous 
degeneration.  On  the  other  hand.  Benda  has  stated  that  in  Basedow's  dis- 
ease the  glandular  hA-pophysis  is  small.  The  statements  as  to  the  physio- 
logical correlations  between  the  two  ductless  glands  evidently  do  not  agree. 
Of  greater  clinical  interest  seem  to  me  the  pathological  correlations  between 
hypophysis  and  thyroid. 

I  alread}^  have  often  referred  to  this  question.  Thus  in  endemic  cretinism 
wx  have  seen  that  not  the  thyroid  alone,  but  mostly  also  the  h}-pophysis  is 
strumously  degenerated.  Josefson  reports  associated  hyperplasia  of  the 
hypophysis  in  a  case  of  congenital  struma  of  the  thyroid  gland.  Also  quite 
other  kinds  of  processes  seem  to  occur  spontaneously  in  the  two  ductless 
glands.     Thus  Rosenhaupt  reports  a  case  of  sarcoma  of  the  anterior  lobe  of 


324  THE    DISEASES    OF    THE    HYPOPHYSIS 

the  hypophysis,  in  which  there  was  also  a  similar  tumor  of  the  thyroid 
gland.  We  have  also  seen  that  in  acromegaly,  often  manifestations  of 
hx-perthyrosis  occur,  or,  especially  in  the  later  stages,  hyperthyrosis  with 
corresponding  pathologico-anatomical  alterations  of  the  thyroid  gland. 
Moreover,  we  shall  see  later  that  in  multiple  ductless  glandular  sclerosis, 
the  sclerotic  process  affects  almost  regularly  thyroid  gland  and  hypophysis. 
A  slight  degree  of  the  thyroid  gland  insulhciency  does  not  seem  to  be  rare 
also  in  hypophysial  dystrophy — at  least,  a  myxedemoid  pufhness  of  the  face 
may  be  observed,  especially  in  the  later  stages.  Finally,  the  h\'pophysis 
may  degenerate  also  in  the  later  stages  of  Basedow's  disease.  I  would  sur- 
mise this,  because  in  such  cases  are  found  characteristic  fat-deposits  and 
swellings  of  the  skin  that  remind  one  of  myxedema,  while  the  hyperthyrosis 
still  continues  and  shows  a  great  sensitiveness  against  thyroidin. 

All  this  points  to  the  fact  of  an  uncommonly  intimate  pathological  corre- 
lation between  h}^ophysis  and  thyroid  gland,  that  is  well  adapted  for  the 
complication  of  chnical  pictures. 

Differential  Diagnosis.- — The  first  question  to  be  decided  in  the  matter  of 
differential  diagnosis  is  as  to  whether  an  existing  adiposo-genital  dystrophy  is 
of  hypophysial  origin,  or  whether  the  individual  is  a  eunuchoid;  if  the  latter  is 
the  case,  of  course  all  symptoms  of  brain  pressure  are  absent,  and  the  X-ray 
plate  shows  a  sella  of  normal  size.  But  it  should  not  be  forgotten  that  also 
in  hypophysial  dystrophy,  the  sellar  alterations  and  the  pressure  symptoms 
may  be  absent,  if  gummata,  tubercles,  or  sclerotic  processes  cause  a  dis- 
turbance of  function  of  the  hypophysis.  Perhaps  also  in  many  cases  the 
examination  of  the  respiratory  metabolism  might  be  used  for  purposes  of  dif- 
ferential diagnosis.  ]\Iarked  reduction  of  it  would  probably  only  occur  when 
the  case  is  one  of  hypophysial  dystrophy.  Of  course,  many  more  investiga- 
tions in  this  direction  are  necessary.  Probably  the  ossification  conditions  are 
important  from  the  standpoint  of  dift'erential  diagnosis.  In  primary  genital 
dystrophy  certain  epiphysial  junctures  remain  open  until  high  age,  and  there 
occurs  tallness  and  growth  beyond  the  [age]  growth  Hmits  of  normal.  In 
severe  cases  of  hypophysial  dystrophy  there  occurs,  on  the  contrary,  an  inhibi- 
tion of  development  in  the  occurrence  of  the  bone-nuclei  and  also  dwarfism, 
and  the  epiphysial  junctures  apparently  remain  open  less  long. 

The  differential  diagnosis  from  tumors  of  the  pineal  gland  may  be  at- 
tended with  difficulty.  In  the  cases  of  pineal  gland  tumor  that  begin  in  early 
life  the  diagnosis  is  easy,  as  here  is  also  found  a  premature  development  of 
the  genitalia.  But  even  in  youthful  cases,  the  tumor  of  the  pineal  gland 
may  under  circumstances  restrict  the  function  of  the  hypophysis,  so  that  the 
picture  may  become  admixed  with  features  of  the  hypophysial  insufficiency 
(see  the  case  of  Raymond  and  Claude,  in  the  chapter  on  the  epiphysis). 

Also  the  distinguishing  of  hypophysial  dystrophy  from  multiple  ductless 
glandular  sclerosis  may  present  difficulties,  as  there  exist  cases  that  are 


HYPOPHYSIAL    DYSTROPHY  325 

associated  with  marked  cachexia.  This  we  saw.  for  instance,  in  case  G 
(Observation  XLV).  Very  marked  retrogression  of  the  genitalia  and  of  the 
secondary  sexual  characters  leads  one  to  think  of  associated  involvement  of 
the  suprarenal  cortex.  Attention  should  also  be  especially  directed  to  myx- 
edematous skin  alterations  and  to  pigmentations,  hypotonia,  and  reduction  in 
the  amount  of  sugar  in  the  blood.  When  these  symptoms  are  present,  we 
should  consider  the  associated  involvement  of  the  thyroid  gland  or  of  the 
chromaffin  tissue.  In  an  adiposo-genital  dystrophy  of  hA-pophysial  origin, 
the  exact  differentiation  of  the  processes  that  lead  to  an  impairment  of  the 
hypophysis  is  often  A'ery  difficult  or  impossible;  and  yet  this  would  be  of 
great  practical  importance  for  the  indications  for  operation.  Here  the  X-ray 
examination  furnishes  important  information. 

Tumors  that  proceed  from  the  M-pophysial  apparatus  itself,  deepen,  when 
they  lie  intrasellarly,  the  floor  of  the  sella.  If  they  proceed  from  the  hypo- 
physial duct  they  dilate  chiefly  the  sellar  introitus,  but  can  also,  if  they  are 
large,  deepen  the  floor  of  the  sella.  An  intracranial  process  chiefly  sharpens 
the  clinoid  processes  to  a  point  (Erdheim.  SchiiUer) .  Later  it  may  erode  them. 
Then  the  X-ray  would  readily  lead  to  faulty  conclusions;  in  such  cases  ero- 
sions are  mostly  found,  however,  in  other  places.  Exceptionally  a  similar 
destruction — here  I  follow  the  dissertation  of  Schuller — may  be  produced  by 
an  aneurysm  of  the  carotid  artery,  by  an  endothehoma  of  the  dura  mater,  or 
by  basal  tumors  of  the  middle  fossa  of  the  skull.  In  tuberculous  caries  or  in 
primary  tumors  of  the  body  of  the  sphenoid  bone,  the  infiltration  of  the 
sphenoid  bone  is  shown  in  the  X-ray  plate,  thus  enabling  dift'erentiation. 
Finally  the  clinoid  processes  may  be  eroded  and  sharpened  from  behind  by 
tumors  of  the  cerebello-pontile  angle.  The  flner  details  of  the  bone  erosions 
are  alone  of  value  for  the  X-ray  diagnosis,  for  as  Schuller  mentions,  the 
tumors  themselves  are  only  visible  in  the  X-ray  picture  when  they  calcify  or 
when  they  penetrate  in  one  of  the  pneumatic  cavities  of  the  skull.  Apart 
from  the  X-ray  examination,  the  presence  of  early  pressure  symptoms  on  the 
part  of  the  more  distant  cranial  nerves  or  symptoms  of  a  hydrocephalus 
speak  against  the  primary  involvement  of  the  hypophysial  apparatus. 

Treatment. — To-day  operation  stands  in  the  mid-point  of  therapy. 
Schlofer  and  v.  Eiselsherg  in  the  cases  of  r.  Frankl-Hochwart.  0.  HirscJi,  and 
Cushing  first  carried  out  operation  in  h}'pophysial  adiposo-genitahs,  with 
partial  good  results.  The  methods  now  used  are  all  intracranial.  Schloffer 
and  V.  Eiselsherg  made  a  path  to  the  h\'pophy5i5  by  making  a  flap  of  the  nose, 
0.  Hirsch  by  operating  endonasally.  The  result  consisted  at  all  events  chiefly 
only  in  the  combating  of  the  symptoms  of  brain  pressure;  the  tormenting 
headaches  disappeared,  and  the  visual  power  improved,  but  only  in  few  cases 
did  there  result  in  addition  a  recession  of  the  dystrophic  manifestations,  and 
did  the  patients  lose  some  kg.  of  their  fat;  in  certain  cases  hair  even  disap- 
peared on  the  pubis  and  in  the  axillae;  in  one  case  erections  occurred,  in 


326  THE    DISEASES    OF    THE    HYPOPHYSIS 

another  a  slight  menstrual  hemorrhage  was  observed  some  months  after  the 
operation.  The  improvement  in  the  blood  picture  after  operation  is  notice- 
able in  Observation  XXXIV.  Also  the  mental  condition  changed,  and  the 
patient  was  much  more  impressionable.  Even  the  combating  of  the  pres- 
sure symptoms  alone  and  the  saving  from  complete  blindness  might  in 
themselves  be  regarded  as  a  striking  result;  extreme  care  must  always  be 
taken  in  considering  the  indications  for  or  against  operation.  Apart  from 
the  danger  of  the  operation  we  should  consider  that  the  surgeon  should  not 
remove  just  that  part  of  the  hypophysis  that  functionates,  thereby  increasing 
the  dystrophic  manifestation  and  eventually  bringing  on  a  cachexia.  The 
operation  is  therefore  only  indicated  in  tormenting  symptoms  of  brain  pres- 
sure or  in  rapid  increase  of  the  visual  disturbance.  The  tumor  tissue  can- 
not be  radically  removed  by  any  of  the  methods  named.  Therefore  no  case 
without  relapse. 

The  conception  of  dystrophia  adiposo-genitalis  as  hypopituitarism  leads 
us  to  expect  results  from  a  therapy  by  administration  of  hypophysial  sub- 
stance. Levy  and  Rothschild,  Axenjeldt  and  Delille,  as  well  as  Ciishing,  claim 
to  have  seen  good  results.  In  one  case  I  also  saw  a  striking  improvement. 
Leman  and  van  Wart  after  the  administration  of  hypophysis  tablets  saw  a 
growth  of  hair  on  the  torso.  The  tumor  symptoms  (hemianopsia,  etc.)  are 
naturally  not  improved  by  this  treatment.  Thyroidin  may  be  used  with 
effect  against  the  obesity.  In  cases  with  marked  tormenting  symptoms  of 
cerebral  pressure  in  which  a  radical  operation  is  not  possible  or  does  not  seem 
advisable,  palliative  trephining  or  Anton's  "Balkanstich"  [puncture  of  the 
corpus  callosum]  brings  rehef.  Finally  it  should  be  mentioned  that  Beclere 
saw  improvement  of  the  visual  disturbance  after  X-ray  irradiation. 

Therapeutic  Use  of  Hypophysis  Extracts. — While  in  the  treatment  of  hypo- 
physial diseases  even  the  use  of  preparations  from  the  hypophyses  of  animals 
has  not  as  yet  won  general  recognition,  yet  the  extracts  from  the  pars  inter- 
media or  the  posterior  lobe  of  the  hypophysis,  pituitrinum  (pituitrinum 
infundibulare  is  a  preferable  designation)  have  rapidly  acquired  a  place  in 
gynecology  and  obstetrics.  The  investigations  of  v.  Frankl-Hochwart  and 
Frbhlich  have  justilied  our  using  them  in  postpartum  bleedings.  Fogcs  and 
Hojstdtter  in  Vienna  and  simultaneously  Bell  in  England  first  reported  the 
favorable  influence  on  hemorrhages  after  labor,  in  which  the  tendency  of  the 
uterus  to  contraction  was  heightened  by  the  preparation.  The  agent  may  be 
used  intramuscularly  as  well  as  intravenously  (1-2  cc.  in  20  cc.  physiological 
salt  solution)  (Hofbauer).  In  the  numerous  experiments  of  Foges  and  others, 
it  was  found  to  be  entirely  harmless.  The  agent  is  especially  valuable  for 
Cesarean  section.  Lately  its  use  has  been  commended  for  hemorrhage  from 
the  nongravid  uterus  (Bab).  It  is  also  recommended  in  postoperative 
paresis  of  the  bladder  (Hofstdtter).  The  voluminous  literature  pertaining  to 
the  subject  is  found  in  the  works  of  J.  Novak  and  of  C.  Hccke.     Finally  there 


ADDENDUM  327 

are  statements  as  to  the  treatment  of  osteomalacia  with  pituitrinum  infun- 
dibulare  {Bondi,  Pal,  Bah,  Neu).  Its  use  as  a  cardiac  and  vascular  tonic  has 
not  as  yet  been  tested.  As  when  it  is  injected  subcutaneously  in  man  it  can 
increase  blood-pressure  not  inappreciably  and  for  a  long  time,  tests  in  this 
direction  seem  to  me  very  desirable,  the  more  so  as  disagreeable  by-actions  are 
very  much  rarer  than  when  adrenalin  is  used.  As  pituitrinum  infundibulare 
increases  the  respiratory  metabolism,  Bernstein  and  /  have  tried  it  in  one  case 
of  adiposity,  without  result. 

Pituitrinum  glandulare  has  been  tested  but  little.  Very  interesting  is 
the  statement  of  Pal  that  two  cases  of  osteomalacia  that  were  treated  with 
extract  of  anterior  lobe  {Parke,  Davis  b'  Co.)  improved  essentially. 

Addendmn 

The  subject  of  acromegaly,  always  an  interesting  one,  has  been  so 
thoroughly  dealt  with  by  the  author,  and  so  much  has  been  written  about 
it,  especially  in  this  country,  by  Gushing,  that  the  editor  feels  he  has  nothing 
to  add.  The  author  is  perhaps  a  trifle  misleading  in  the  portion  of  the 
chapter  that  deals  with  hypophysial  dystrophy,  conveying  the  impression 
that  all  cases  of  pituitary  tumor  that  cause  this  affection  are  associated 
with  the  characteristic  fat  distribution.  Whether  this  is  so  is  questionable, 
although  authors  who  have  reported  such  cases  do  not  always  take  pains 
to  deny  that  such  a  distribution  is  present,  v.  Frankl-Hochwart  himself 
did  not  find  it  in  the  case  reports  that  he  reviewed,  and  in  some  of  these 
reports  an  emaciation  was  spoken  of.  In  eleven  of  his  own  cases  it  was 
present  pronouncedly  in  eight,  and  was  only  suggested  or  indicated  in  three. 
V.  Frankl-Hochwart  points  out  that  the  cases  more  nearly  approach  the 
classic  types  the  earlier  in  life  the  disease  sets  in. 

Wolf  stein  in  reporting  a  case  of  hypophysial  tumor  calls  attention  to  the 
importance  of  bitemporal  hemichromatopsia  in  the  early  diagnosis.  In  this 
author's  case  the  pubic  and  axillary  hair  did  not  fall  out,  although  there 
was  a  sudden  cessation  of  menstruation. 

Sweet  and  Allen  have  done  apparent  total  hypophysectomy  in  dogs,  with 
characteristic  changes  in  the  animals  but  not  death.  They  believe  that  in 
the  dog  the  entire  gland  can  be  removed  without  danger  to  life. 

Recent  experiments  of  Herring  make  it  appear  as  though  there  are  two 
separate  active  principles  in  the  posterior  lobe  of  the  hypophysis.  It  is 
probable,  that  the  active  principle  of  the  posterior  lobe  is  a  product  of  the 
epithelial  cells  of  the  pars  intermedia,  and  that  there  are  in  the  pars  nervosa 
certain  products  of  the  breaking  down  of  these  cells.  The  substance  acting 
upon  the  uterus  is  formed  at  an  early  stage  in  the  cells  of  the  pars  intermedia, 
but  the  substance  acting  on  the  blood  pressure  and  kidney  is  a  later  product 


328  THE    DISEASES    OF    THE    HYPOPHYSIS 

resulting  from  the  breaking  down  in  the  pars  nervosa,  of  the  hyaline  bodies, 
or  the  disintegrating  pars  intermedia  cells. 

Gcstsch  has  recently  ascertained,  as  the  result  of  numerous  experiments, 
that  extract  of  anterior  lobe  of  pituitary  body  (representing  pituitrinum 
glandulare),  when  fed  to  young  rats,  has  a  stimulating  effect  upon  the  growth 
of  the  animal  and  upon  its  sexual  development  and  activity.  Posterior  lobe 
extract  (representing  pituitrinum  infundibulare),  when  given  in  the  same 
manner,  has  a  retarding  influence. 

O p penheim  calls  attention  to  the  fact  that  both  tabes  and  general  paralysis 
may  be  closely  simulated  by  pathological  processes  affecting  the  hypophysis. 
Among  the  efifects  of  such  processes  may  be  a  simple  optic  atrophy  and 
evidences  of  true  posterior  column  degeneration.  These  symptoms  have 
nothing  to  do  with  the  presence  of  the  tumor  per  se,  that  is,  they  are  not  due 
to  pressure,  for  instance,  nor  are  they  due  to  a  true  tabetic  or  paretic  process, 
but  are  due  to  the  alteration  (quantitative  or  quahtative)  of  function  of  the 
ductless  glands. 

Referen'ces 

dishing  (H.).  Pituitary  body  and  its  disorders.  Phila.  and  London,  J.  B.  Lippincott 
Co.,  1912. 

dishing  (H.).  Concerning  the  symptomatic  differentiation  between  disorders  of  the 
two  lobes  of  the  pituitary  body;  with  notes  on  a  syndrome  accredited  to  hyperplasia  of  the 
anterior  and  secretory  stasis  or  insufficiency  of  the  posterior  lobe.  Am.  J.  M.  Sc,  March, 
191,3,  PP-  313-  328. 

V.  Frankl-Hochwarl  (L.).  Die  Diagnostik.  der  Hj^pophysistumoren  ohne  Akrome- 
galie.  Wien.  med.  Wcnsch.,  1909,  37,  p.  2127,  38,  p.  2297,  39,  p.  2326,  1909,  37,  p. 
2127,  s^,  P-   2257. 

Wolf  stein  {D.  J.).  Tumor  and  clinical  pathology  of  the  hypophysis.  Lancet- 
Clinic,  Vol.  CVm,  Oct.  5,  1912,  pp.  365-373. 

Sweet  {J.  E.)  and  Allen  {A.  R.).  The  effect  of  removal  of  the  hypophysis  in  the 
dog.     Annals  of  Surgery,  58,  1913,  p.  485. 

Herring  {P.  T.).  The  physiological  activity  of  the  pars  intermedia  and  pars  nervosa 
of  the  ox  pituitary  quantitatively  compared.  Quarterly  journal  of  Physiology,  Vol.  VIII, 
19,  pp.  267-274. 

Gcetsch  (£.).  The  influence  of  pituitarj'  feeding  upon  growth  and  sexual  develop- 
ment. An  experimental  study.  Bulletin  of  the  Johns  Hopkins  Hospital,  \'ol.  XX\  II, 
No.  300,  Feb.  1916,  p.  29-50. 

Op  penheim  (H.).  Uber  Vortaiischung  von  Tabes  und  Paralyse  durch  Hypophysis- 
tumoren  (Pseudotabes  pituitaria,  etc.).     Ztschr.  f.  d.  ges.  neurol.   u.  psychiat.,  i,  1914, 

XXV,  pp.  527-535- 


CHAPTER  VII 

THE  DISEASES   OF  THE  EPIPHYSIS    (GLANDULA   PINEALIS, 
"ZIRBELDRUSE")   [CONARIUM] 

Anatomy  and  Embryology. — The  epiphysis  originates  from  an  extrusion 
from  the  roof  of  the  third  ventricle.  About  the  fifth  month  of  fetal  Kfe  there 
develops  between  the  posterior  commissure  and  the  habenular  commissure 
a  thin  epithehal  extrusion  that  later  thickens  and  penetrates  the  mesodermal 
tissue.  The  epiphysis  in  many  of  the  animal  classes,  for  instance  the  reptiles, 
is  very  well  developed,  and  in  the  developed  human  being  it  constitutes  a 


Fig.  63. — Epiphj'sis  of  man. 

fiat  body  that  arches  forward,  about  i  cm.  long  and  0.5  cm.  broad,  which  by 
the  dorsal  lip  comes  into  connection  with  the  habenular  commissure  and  by 
the  ventral  with  the  posterior  commissure.  Between  the  two  lips  the  recessus 
pinealis  extends  from  the  third  ventricle  into  the  gland.  In  the  new-born  it 
is  more  spherical,  and  contains  regular  folhcles  with  polygonal  cells,  and, 
toward  the  recess,  ghal  tissue.  Commencing  with  the  seventeenth  year  there 
begin  signs  of  involution,  increase  of  the  connective  tissue  and  glia;  the  fol- 
licles sometimes  form  cysts  or  contain  concrements,  the  so-called  brain  sand. 

329 


330  THE    DISEASES    OF    THE    EPIPHYSIS 

Pathological  Anatomy. — The  diseases  of  the  epiphysis  known  up  to  the 
present  time  consist  chiefly  in  cyst  formations,  gummata,  and  tumors. 
Neumann  has  collected  twenty  tumors  from  the  literature  and  adds  two  of  his 
own;  they  were  sarcomata,  carcinomata,  teratomata,  gliomata,  psammomata, 
and  cysts.  The  individuals  affected  were  chiefly  youthful  so  that,  as  Neumann 
supposes,  the  underlying  factors  might  well  be  chiefly  developmental  an- 
omalies; these  are  very  much  more  frequent  in  the  male  sex.  The  terato- 
mata contain  hair  folUcles,  sebaceous  glands,  cartilage,  fat,  smooth  muscle 
fibers,  etc.  {Weigert  and  others). 

S3miptomatology. — The  symptoms  that  are  produced  by  these  lesions 
of  the  epiphysis  are  on  the  one  hand  local  symptoms,  on  the  other  hand  char- 
acteristic trophic  disturbances.  The  first  are  caused  by  the  pressure  of  the 
enlarged  organ  on  the  neighboring  brain  structures  (thalamic  and  subthala- 
mic regions,  pulvinar,  pons,  cerebellum,  corpus  callosum,  etc.),  and  through 
congestion  in  the  brain  ventricle.  If  the  tumor  grows  backward,  congestion 
in  the  fourth  ventricle  occurs  on  account  of  closure  of  the  aqueduct  of 
Sylvius;  if  it  grows  forward,  there  occurs  hydrocephalus  of  the  third  and 
lateral  ventricles.  The  pressure  symptoms  consist  in  motor  symptoms  of 
irritation  or  paralysis,  ophthalmoplegias,  conjugate  deviation,  alteration  of 
the  pupillary  reactions,  nystagmus,  ataxia,  epileptiform  convulsions  (mostly 
bilateral),  pareses,  rigidity  of  the  neck,  choked  disc,  or  more  rarely  genuine 
atrophy,  difficulty  in  hearing,  vertigo,  headaches,  vomiting  and  eventually 
slowing  of  the  pulse,  lethargy,  symptoms  that  are  common  also  to  all  the 
tumors  of  the  quadrigemina. 

In  addition  to  these  symptoms  there  occur,  if  the  tumor  develops  in  early 
childhood,  characteristic  trophic  disturbances  that  consist  in  an  abnormally 
rapid  bodily  development  and  in  a  premature  development  of  the  genitalia, 
and  are  uncommonly  similar  to  those  which  we  shall  consider  under  adeno- 
mata of  the  suprarenal  cortex.  To  this  group  belong  the  cases  of  Ostreich- 
Slavyk,  Ogle,  Marburg,  v.  Frankl-Hochwart,  and  Raymond  and  Claude. 
Throughout  the  cases  were  those  of  children  under  ten  years  of  age. 

In  the  case  of  Ogle,  the  premature  development  of  the  genitalia  w^as  very 
considerable.  It  was  the  case  of  a  six-year-old  boy  who  died  with  the  mani- 
festations of  a  brain  tumor.  Lately  the  boy  had  masturbated.  The  penis 
was  developed  like  that  of  a  seventeen-year-old  youth.  There  was  an  abun- 
dance of  hair  on  the  mons  veneris.  The  testicles  were  apparently  not  en- 
larged. Autopsy  showed  an  alveolar  sarcoma  of  the  pineal  body.  The  case 
of  Oslreich-Slavyk  was  that  of  a  four-year-old  boy  who  from  the  third  year  of 
life  had  shown  a  striking  body  development;  the  penis  was  9  cm.  long,  the 
genitals  w^ere  covered  with  hair  i  cm.  long.  The  boy  was  108  cm.  tall  and 
weighed  20  kg.;  these  measurements  correspond  with  those  of  a  seven-  to 
eight-year-old  boy.  The  mammaj  were  hypertrophic  and  contained  colos- 
trum.    At    the    beginning   also  voracious    hunger   existed,   but   later   this 


sy:^iptoaiatology  331 

disappeared.  The  case  was  also  described  by  Heuhner.  The  case  of  v. 
Frankl-HocJiii'art  was  that  of  a  hve-and-one-hah-year-old  child,  whose  body 
length  corresponded  to  that  of  a  nine-year-old  boy;  the  development  of  the 
penis  and  of  the  entire  genitalia  and  the  secondary  sexual  characters  cor- 
responded \\ith  those  of  a  tif teen-year-old  boy;  frequently  erections  oc- 
curred. The  voice  was  deep,  and  in  addition  there  was  a  premature  mental 
development  1  thoughts  about  the  immortahty  of  the  soul) ;  also  Ostreich- 
Slai'vk  designated  the  four-year-old  boy  described  by  him  as  '"old-wise" 
[altklug]. 

In  most  cases  the  conditions  of  nutrition  were  started  to  be  very  good.     In 
other  cases — apparently  in   those  which  develop  later — there  occurred  an 
excessive  adiposity.     So  for  example  is  the  case  of  0.  Marburg;  here  we  are 
dealing  vrith.  a  nine-year-old  girl,  in  whom 
right  at  the  beginning  of  the  disease  (eight 
months  ago)  obesity  developed,  that  linally 
became  excessive,   especially  on  the  breast 
and  abdomen.     Autopsy  showed  a  complex 
tumor  of  the  epiphysis  consisting  of  tissue  of 
the  pineal  gland,  the  ependyma.  the  choroid 
plexus,  and  of  gha.     In  addition  to  this  was 
found  a  sHght  colloid  thyroid  gland  struma, 
and  a  sHght  status  lymphaticus;  the  genital 
glands    and    the   h}pophvsis    were   normal. 

^^        .      ,^  '     ,  t       '^  m      i  i        -n     -7  FiG.  64. — Hvnertrophv  of  the ex- 

Also  m  the  case  recentlv  described  bv  Bailex     ^       ,        .    ..      .      f  '       , 

ternai  gemtaiia  ot   a   tour-and-one- 

and  Jelliffe,  that  of  a  twelve-year-old  boy.  half-year-old  boy,  123  cm.  taU  (penis 
there  was  obesitv;  the  genitaha  were  normal.  6  cm.  long,  hair  on  the  mens 
Autopsv  showed  a  teratoma  of  the  pineal     ^''""f^'  according    to  .    FranU- 

'  Hocliwart.   Ztsch.  f.  JServenh..  1900. 

gland. 

In  the  epiphysial  tumors  that  up  to  the  present  have  been  observed  in 
adults  and  adolescents  there  occurred  either  no  especial  trophic  manifesta- 
tions (for  example  in  the  case  of  Xeumann.  twenty-seven-year-old  man,  or  in 
the  case  of  Askanazy,  nineteen-year-old  man)  or  the  trophic  manifestions 
were  quite  of  a  different  kind.  Here  there  occurred  either  adiposity,  which. 
as  in  Miiller's  case  may  attain  an  excessive  degree  (increase  of  55  to  79.5 
kg.  in  weight) ;  other  cases  of  adiposity  in  pineal  gland  tumor  or  of  tumors 
that  destroyed  the  pineal  gland  have  been  described  by  Coats.  Daly.  Fakkson. 
Kny,  Konig.  Xothnagel,  and  others.  Or  in  other  cases  there  develops  a  strik- 
ing cachexia  in  which  the  skin  may  show  a  pasty  consistency.  In  certain 
cases  pohniria  has  been  observed,  in  others  persistence  of  the  thymus  gland, 
in  the  case  of  Xeiimanii  formation  of  a  goiter.  There  may  also  occur  atrophy 
of  the  genitaha  and  of  the  mamnice. 

The  significance  of  all  these  trophic  manifestations  is  not  yet  clear.  As  far  as  the  pre- 
mature   development    that  occurs  in  childhood  is  concerned,  the    great    morphological 


332  THE    DISEASES    OF    THE    EPIPHYSIS 

difference  in  the  tumors  may  be  explained  by  the  fact  that  they  represent  the  failure  or 
insufficiency  [of  function]  of  the  epiphysis.  We  should  therefore  understand  that  nor- 
mally in  childhood  inhibitory  influences  on  development  proceed  from  the  pineal  gland, 
which  gradually  fall  away  or  become  slighter  with  the  partial  involution. 

This  view  has  been  especially  developed  by  Marburg.  Marburg  beheved 
that  hypopinealism  leads  to  premature  development  of  the  genitalia,  hyper- 
pinealism  to  universal  obesity  and  apinealism  to  cachexia.  The  interpre- 
tation of  adiposity  as  h>Tperpinealism  is  no  longer  held  to  be  correct,  even 
by  Marburg.  It  may  very  well  come  about  through  disturbance  of  the  hypo- 
physial function;  one  may  see  very  well  that  the  pineal  gland  tumors  may 
behave  in  this  respect  just  like  other  processes  that  increase  cerebral  pressure, 
the  more  so  because  on  account  of  their  position  they  lead  to  stagnation  in 
and  dilatation  of  the  third  ventricle.  The  interpretation  of  the  premature 
development  as  hypopinealism  has  recently  been  supported  by  animal  ex- 
perimentation. Exner  and  Boese  could  not  indeed  observe  a  premature 
development  after  extirpation  of  the  epiphysis  in  young  animals.  C.  Fod, 
however,  saw  after  extirpation  of  the  epiphysis  in  young  fowls  a  premature 
and  extraordinary  development  of  the  testicles  and  some  of  the  secondary 
sexual  characters.  Extirpation  of  the  sexual  glands  in  youth  produces  in 
male  and  female  animals  atrophy  of  the  epiphysis  {Biach  and  H idles). 
Askanazy  beheves  that  every  embryonal  teratoma  is  to  be  regarded  as  a 
sort  of  pseudopregnancy  that  should  lead  to  a  premature  maturation  and  a 
premature  development  of  the  genital  sphere,  a  view  that  Hart  accepts,  while 
Pappenlieimer  opposes  it.  I  do  not  regard  it  as  impossible  that  the  trophic 
influences  of  the  pineal  glandular  tumors  in  early  life  go  over  the  suprarenal 
cortical  system,  [hyperplastic  development  of]  which  also  leads  to  premature 
maturation  and  premature  development  of  the  genitals  (see  the  following 
chapter). 

At  least  it  should  be  noticed  that  in  one  case  Raymond  and  Claude  found 
hyperplasia  of  the  suprarenal  cortex.  I  will  quote  this  interesting  case  in 
greater  detail.  It  was  that  of  a  ten-year-old  boy.  The  disease  began  in  the 
seventh  year  of  life  with  gradual  blindness  and  increasing  adiposity.  The  boy 
at  the  age  of  ten  years  was  138  cm.  tall  (about  corresponding  to  a  thirteen- 
year-old  boy)  and  weighed  39  kg.  Much  fat  had  accumulated,  especially  on 
the  abdomen  and  on  the  hips.  The  pubic  hairs  were  well  developed  and  there 
was  a  foreshadowing  of  a  beard  on  the  upper  lip.  Penis  and  testicles  were 
small.  Histologically  the  testicles  showed  no  spermatogenesis,  but  the  inter- 
stitial glands  were  very  well  developed.  The  less  strong  predominance  of 
the  premature  genital  development  could  in  this  case  have  been  brought 
about  through  a  restriction  in  the  function  of  the  hypophysis;  for  the  epiphy- 
sial tumor,  which  was  the  size  of  an  apple,  had  led  to  a  marked  dilatation 
of  the  lateral  and  the  third  ventricles  and  to  a  marked  flattening  of  the 
hypophysis. 


ADDENDUM  333 

The  diagnosis  of  epiphysial  tumors  in  adults  is  hardly  possible,  as  the 
symptoms  produced  are  hardly  to  be  distinguished  from  the  tumors  of 
the  neighborhood  of  the  corpora  quadrigemina. 

According  to  Marburg  the  possibility  of  an  epiphysial  tumor  should  be 
thought  of  when  there  occurs  associated  symptoms  of  initial  headaches — 
especially  of  the  occipital  region — early  choked  disc,  vertigo,  sleeplessness, 
convulsions,  later,  somnolence,  paralysis  of  the  eye  muscles  associated  with 
ataxia  (Nothnagel),  and  disturbances  in  hearing.  What  makes  the  diagnosis 
the  more  difhcult  is  that  epiphysial  tumors,  as  above  mentioned,  also  lead  to 
dystrophia  adiposo-genitalis,  probably  through  limitation  of  the  function  of 
the  hypophysis.  On  the  contrary,  the  diagnosis  in  childhood  is  possible, 
through  the  combination  of  general  brain  tumor  symptoms  and  those  of 
quadrigeminal  lesion  with  those  of  premature  development  of  the  body,  the 
psyche,  and  the  genital  sphere,  and  was  first  made  in  vivo  by  v.  Frankl- 
Hochwart.     The  treatment  by  operation  has  not  as  yet  been  tried. 

Addendum 

Jordan  finds  no  clear  histological  evidence  indicative  of  a  glandular  func- 
tion of  the  pineal  body,  and  that  if  the  pineal  body  in  the  sheep  subserves  an 
important  physiological  function,  this  is  probably  active  only  during  the  first 
eight  months  of  postnatal  life.  Pineal  bodies  of  sheep  older  than  one  year 
present  much  variation  and  degeneration. 

An  editorial  in  the  Journal  of  the  American  Medical  Society,  Vol.  LXVT,  No.  5, 
Jan.  29,  1916,  p.  361,  calls  attention  to  the  stimulating  effects  of  pineal  gland  extracts 
when  administered  to  young  animals,  and  to  negative  results  following  extirpation  of 
the  pineal  gland.  The  literature  dealing  with  the  material  of  this  apparent  incon- 
gruence will  be  found  in  conjunction  with  Walter  E.  Dandy's  article:  Extirpation  of  the 
pineal  gland,  Journal  of  Experimental  Medicine,  Vol.  XXII,  No.  2,  Aug.  i,  1915,  p. 
237-247. 

Jordan  (H.  E.).  The  histogenesis  of  the  pineal  body  of  the  sheep.  Am.  J.  Anat., 
Vol.  XII,  1911-12,  pp.  249-270. 


CHAPTER  VIII 


THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

Anatomy  and  Embryology.^ — The  suprarenals  are  paired  organs,  that  rest 
hook-hke  on  the  upper  pole  of  the  kidneys.  Their  breadth  according  to 
V.  Xeusser  and  Weisel,  is  about  40-50  mm.,  their  height  30-35  mm.,  their 
thickness  2-8  mm.,  their  weight  averages  10.6  gm.  in  women  and  11.6  gm.  in 


Fig.  65. — Suprarenal  gland  of  man.     C.  =  capsule,  Cor.  =  cortex,  M.  =  medulla,  Z.gl.  =  zona 
glomerulosa,  Z.f.  =  zona  fasciculata,  Z.r.  =  zona  reticularis. 

men.  They  are  made  up  of  two  embryologically  independent  parts,  the  cor- 
tex and  the  medulla.  The  so-called  intermediary  zone  belongs  to  the  cortex. 
The  cortex  is  made  of  columns  of  cells,  which  cells  are  filled  with  glistening 
granules,  most  doubly  refractile,  of  a  lipoid  character.  The  medulla  con- 
tains numerous  nerves  and  multipolar  ganglion  cells,  and  in  addition  nests 

334 


ANATOMY  AND  EMBRYOLOGY  335 

of  cells,  which  take  a  brown  color  when  they  are  stained  with  chromic  acid, 
and  a  green  stain  with  iron  chloride.     They  are  termed  chromaffin  cells. 

From  the  arteries  of  the  diaphragm,  from  the  aorta,  and  also  from  the  renal  artery,  re- 
spectively, are  given  off  a  branch  to  the  suprarenal  glands.  These  form  subcapsularly  an 
anastomosis,  from  which  the  cell  columns  of  the  cortex  are  surrounded  by  a  fine  capillary 
network,  and  which  also  continues  into  the  medulla;  moreover  there  are  the  so-called 
arteriae  perforantes,  which  run  through  the  cortex  and  first  form  a  capillary  network  in 
the  medulla.     The  suprarenal,  veins  empty  into  the  vena  cava. 

True  accessory  suprarenals  that  are  made  up  of  cortex  and  medulla  are 
rare.  On  the  contrary  accumulations  of  chromaffin  tissue  may  exist  outside 
the  suprarenals.  The  larger  have  been  termed  ^'' paraganglia^^  by  Kohn. 
Such  cell  accumulations  are  found  on  the  carotid  artery,  in  the  ganglia  of  the 
sympathetic  trunks  and  in  the  solar  plexus,  in  the  left  stellate  ganglion,  on 
the  site  of  giving  off  of  the  left  coronary  artery  and  superior  mesenteric,  at 
the  hilus  of  the  kidney,  and  along  the  course  of  the  sympathetic  nerves 
(Zuckerkandl,  Kohn).  In  the  adult  the  total  amount  of  the  extramedullary 
chromaffin  tissue  is  not  smaller  than  the  medullary  part;  in  the  new-born 
it  is  greater.  Accumulations  of  cortical  substance  can  be  found  at  the  hilus 
of  the  kidney,  in  the  renal  substance  itself,  along  the  suprarenal  veins,  and 
in  the  internal  genitalia.  Schmorl  found  them  in  92  per  cent,  of  cases,  Weisel 
in  the  genitalia  of  new-born  boys  in  76.5  per  cent.  Aichel  found  them  never 
absent  in  the  broad  ligament  of  new-born  girls.  Some  of  these,  also,  later 
retrogress. 

Embryological  and  phylogenetic  studies  agree  with  the  anatomical  that 
the  suprarenal  apparatus  consists  of  two  independent  systems  which  in  the 
lower  classes  of  animals  are  arranged  segmentally  and  remain  separated  per- 
manently. The  chromaffin  or  adrenal  system  is  of  ectodermal  origin  and  is 
part  of  the  sympathetic. 

Already  at  a  very  early  period  the  primitive  cells  separate  into  two  differ- 
ent forms,  into  the  primitive  form  of  the  sympathetic  nerve  cells  and  into  the 
so-called  phaeochromoblasts,  from  which  the  chromaffin  cells  originate.  The 
cortical  tissue — the  so-called  interrenal  system — develops  from  the  ventral 
part  of  the  mesoderm  and  indeed  quite  in  the  neighborhood  of  that  place  of 
the  celomic  epithelium  from  which  the  sexual  glands  originate;  suprarenal 
cortex  and  sexual  glands  are  laid  out  in  the  Wolffian  duct,  which  explains  the 
topography  of  accessory  suprarenals  consisting  in  cortex  alone  along  the 
entire  way  that  the  sexual  glands  travel,  indeed  even  in  the  sexual  glands  and 
kidneys  themselves  (Soulie).  During  fetal  life  the  suprarenal  is  at  first 
larger  than  the  kidney,  and  at  birth  is  about  the  same  size.  Already  at  an 
early  period  some  of  the  chromaffin  cells  have  broken  through  the  complex  of 
cortical  cells  to  form  the  medulla.  Through  the  descent  of  the  genital 
organs  small  parts  of  both  systems  are  displaced.  This  shows  that  the 
former  complete  physiological  independence  of  both  systems  later  gives  place 


336  THE    DISEASES    OF    THE    SUPRAREXAL    APPARATUS 

to  a  common  function,  at  least  in  part  (Biedl).  which  fact  is  also  indicated  by 
the  previously  mentioned  relations  of  the  blood-vessels.  It  is  indispensable 
for  the  comprehension  of  diseases  of  the  suprarenals  to  consider  that  the  two 
systems  for  a  great  part  are  functionally  independent.  The  higher  we  go  in 
the  classes  of  animals,  the  greater  become  the  complexes  of  the  two  systems 
that  finally  unite  to  form  a  single  organ,  the  suprarenal. 

a.  Conditions  of  Hypofunction  of  the  Suprarenal  Apparatus 
I.  Addison's  Disease 

Definition. — In  the  year  1855  Thomas  Addison  described  the  disease  that 
bears  liis  name.  The  disease  mostly  develops  in  the  third  or  fourth  decades  of 
life,  usuallv  quite  insidiously,  with  adynamia  and  apathy.  To  tJiese  are  added 
disturbances  of  the  digestive  tract  (constipation,  often  alternating  ivith  diarrheas) 
and  pigmenting  of  the  skin  and  the  mucous  membranes;  the  patients  succumb 
under  a  gradually  increasing  cachexia,  not  rarely  ii-ith  stormy  terminal  mani- 
festations; autopsy  almost  always  shows  disease  of  both  suprarenals,  mostly 
tuberculous  caseation.  Addison's  description  embraces  all  the  essential 
features. 

Symptomatology. — The  disease  affects  mostly  indi\-iduals.  often  heredi- 
tarily incHned  to  tuberculosis,  who  have  been  weakly  from  youth.  Mostly 
it  is  individuals  of  middle  age  who  are  affected,  rarely  are  children  or  old 
people  affected.  Almost  always  the  disease  manifests  itself  in  ready  fatiga- 
bihty.  disincUnation  for  work,  and  apathy;  to  these  symptoms  are  sometimes 
added  headaches,  poor  sleep,  sometimes  obstinate  insomnia,  psychical  ill- 
humor  and  depression,  often  too,  abnormal  irritabihty;  further,  diminution 
in  memory,  noises  in  the  ears,  vertigo  and  commonly  fainting  attacks, 
singultus,  and  rheumatoid  pains  in  the  back  and  in  the  extremities,  sometimes 
also  epileptiform  convulsions.  Extremely  stormy  manifestations  on  the 
part  of  the  nervous  system  may.  especially  in  the  later  stages,  make  their 
appearance — violent  dehrium,  acute  confusion,  convulsions,  deep  stupor,  and 
coma.  The  symptoms  on  the  part  of  the  digestive  tract  are  very  various. 
The  patients  complain  about  pressure  in  the  stomach,  eructation,  nausea, 
pyrosis,  sometimes  vomiting  and  epigastric  pains.  In  the  later  stages  there 
are  mostly  lessening  or  absence  of  the  hydrochloric  acid  and  ferment  produc- 
tion. Often  diarrheas  alternate  with  constipation.  The  diarrheas  may 
occur  in  crises  ^s-ith  great  violence,  may  be  associated  with  spasms  of  the 
calves  and  may  simulate  the  picture  in  cholera  nostras.  In  the  terminal 
stages  there  is  often  immitigable  vomiting.  To  this  may  be  added  ab- 
dominal pains  and  constipation;  the  abdomen  is  retracted,  the  abdominal 
walls  are  tense,  the  pulse  becomes  small,  in  short,  there  exists  the  picture  of 
peritonitis  (Ebstein). 

In  the  later  stages  the  adynamia  becomes  prominent.  Early  the  pulse  is 
strikingly  small  and  soft,  the  blood-pressure  reduced,  the  force  of  the  pulse 


ADDISON  S    DISEASE  337 

lowered  (Afunzer).  Dyspnea  ensues  on  slight  physical  exertion.  Edema  is 
almost  never  observed,  even  later.  Arteriosclerosis  is  extremely  rare;  when 
it  is  present,  the  rise  in  blood-pressure  does  not  occur. 

The  blood  picture  always  shows  changes.  The  count  of  erythrocytes 
and  the  hemoglobin  contents  are  almost  always  reduced,  the  leucocyte  count 
is  mostly  normal.  Lymphocytosis  was  first  observed  by  v.  Neusser.  In 
the  cases  from  the  literature  in  which  the  leucocytic  formula  is  given,  espe- 
cially in  the  cases  of  Bittorf  and  Munzer  and  in  those  described  by  myself, 
lymphocytosis  was  always  present.  Hypereosinophilia  is  not  constant. 
Moreover  the  number  of  large  mononuclear  cells  is  often  increased,  and  the 
number  of  neutrophilic  cells  relatively  and  absolutely  much  diminished,  some- 
times to  40  per  cent.  Commonly  there  are  found  in  additionsigns  of  a  status 
lymphaticus;  swelling  of  the  glands,  the  tonsils,  the  papillae  at  the  base  of  the 
tongue,  etc.  Also  hyperplasia  of  the  thymus  was  observed  in  some  cases 
{Weisel,  Kahn,  Hedinger). 

Of  alterations  of  the  metabolism  should  be  mentioned  especially  the 
falling  off  in  weight.  In  very  rare  cases  only  is  observed  corpulency  lasting 
until  death  (Bittorf).  Investigations  as  to  the  fundamental  exchange  are 
not  knowm  to  me.  The  gastrointestinal  disturbances  may  very  well  cause 
the  emaciation.  The  few  investigations  as  to  the  protein  metabolism  are 
too  short  as  to  time.  Wolf  and  Thacher  found  the  endogeneous  uric-acid 
elimination  very  low.  In  three  cases  of  Addison's  disease,  Eppinger,  Rudin- 
ger,  and  /  found  very  high  tolerance  for  grape-sugar  and  absence  of  glycosuria 
after  injection  of  adrenalin.  Also  in  a  case  of  Pollack's  there  was  no  sugar 
after  2  mg.  adrenalin.  Later  0.  Forges  found  pronounced  hypoglycemia  (up 
to  0.033  psr  cent.)  while  in  other  cachexias  the  blood-sugar  picture  lay  nor- 
mally high.  The  finding  of  Forges  that  w^as  corroborated  by  Bernstein  in 
several  cases,  has  therefore  come  to  have  a  diagnostic  value  attached  to  it. 
The  body  temperature  is  often  reduced,  but  w^hen  the  manifestations  become 
violent  there  may  be  found  sudden  increases  in  temperature,  even  to  hyper- 
pyretic  values. 

The  making  use  of  the  diet  is,  so  far  as  there  are  no  diarrheas,  normal; 
frequently  there  is  indicanuria.  In  the  later  stages  are  found  very  frequently 
disturbances  of  the  genital  function,  deficiency  or  absence  of  menstruation, 
in  men  diminution  or  loss  of  sexual  power. 

The  pigmentations  that  are  so  important  from  a  diagnostic  point  of  view 
mostly  begin  on  the  uncovered  parts  of  the  body,  or  on  parts  where  the 
clothing  presses,  or  on  parts  on  which  certain  irritants,  for  instance  plaster, 
have  exerted  their  action.  Sites  of  especial  predilection  are  the  borders  of 
the  lids,  the  areolae  of  the  nipples,  the  linea  alba,  the  genitalia,  the  anal  folds, 
the  folds  of  the  palm;  otherwise  the  palms,  the  soles  and  the  nail  beds  usually 
remain  free.  In  many  cases  too  the  hairs  become  darker.  The  pigmented 
places  are  light  brown  to  dark  brown,  and  in  many  cases  the  entire  body  may 


338  THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

assume  a  bronze  tint.  Pigment  displacements  are  less  frequent.  The  pig- 
mentations of  the  mucous  membranes  are  almost  always  spot-like  and 
blackish-blue.  They  are  found  on  the  borders  of  the  lips,  on  the  mucous 
membranes  of  the  cheeks,  on  the  soft  palate  and  on  the  border  of  the  tongue. 
Pigmentations  of  the  vaginal  and  rectal  mucous  membranes  are  also  observed. 
The  skin  pigment  lies  in  the  deeper  layers  of  the  rete  Malpighii  and  is  iron- 
free.  In  rare  cases  there  is  observed  also  a  combination  of  Addison's  disease 
with  hemochromatosis  (Fod,  Bittorf,  and  others).  The  pigmentation  is  ex- 
traordinarily frequent.  In  the  statistics  of  Lewin,  based  on  five  hundred 
sixty-one  autopsied  cases,  it  was  found  in  72  per  cent.,  and  Bittorf  believes 
that  these  figures  are  too  low. 

The  course  of  Addison's  disease  is  very  manifold.  There  are  peracute 
cases  in  which  destruction  of  suprarenal  is  brought  about  by  hemorrhages, 
thrombosis,  etc.;  in  these  cases  death  may  occur  in  a  few  days  with  stormy 
cerebral  and  intestinal  manifestations.     Pigmentation  is  absent. 

A  short  time  ago  Brodnitz  reported  an  interesting  case  which  I  shall  repeat 
in  detail.  It  was  that  of  a  thirty-six-year-old,  strongly  built,  markedly  fat 
man,  previously  healthy.  Two  and  four  years  ago  there  suddenly  occurred 
violent  intestinal  colics,  which  ceased  after  a  few  hours,  and  were  followed 
only  by  a  marked  loss  of  strength.  Also  at  present  such  a  colic  has  come  on 
quite  suddenly.  The  facial  expression  is  anxious,  the  pulse  hard  and  full, 
50-60  beats  per  minute,  the  temperature  normal  or  slightly  subnormal.  No 
improvement  on  injection  of  morphine.  This  condition  lasted  two  days  and 
was  then  followed  by  an  operation.  On  the  jejunum  and  ileum  were  found 
columnar  contractions  of  10-20  cm.  of  the  intestine  at  three  places.  Other- 
wise conditions  were  normal.  In  the  course  of  the  fourth  day  manifestations 
of  peritonitis  made  their  appearance.  Tympanites  appeared,  the  pulse  was 
soft,  thread-like,  very  rapid.  Vomiting,  temperature  increased  to  39°C. 
Death  on  the  fifth  day.  At  autopsy  was  found  marked  inflation  of  the 
stomach  and  duodenum,  the  small  intestines,  and  the  colon.  No  peritonitis. 
Complete  destruction  of  the  right  suprarenal,  partial  destruction  of  the  left. 
On  microscopical  examination  the  left  suprarenal  at  one  place  showed  marked 
development  of  the  connective  tissue,  with  hemorrhagic  pigment,  in  brief 
signs  of  a  previous  hemorrhage. 

As  a  further  example  I  cite  the  case  of  Karakaschef.  A  young  man  of 
eighteen  years  became  sick  suddenly  with  pains  in  the  head  and  abdomen 
and  felt  very  ill,  but  nevertheless  went  about.  The  manifestations  became 
stronger  only  after  three  days,  when  vomiting  ensued,  and  finally  loss  of  con- 
sciousness. Autopsy  showed  old  total  destruction  of  the  right  suprarenal, 
apparently  through  thrombosis  and  a  quite  fresh  infarction  of  the  left  supra- 
renal.    Death  had  occurred  five  days  after  the  beginning  of  the  illness. 

In  other  cases  the  affection  lasts  for  weeks.  Here  the  adynamia  comes 
more  in  the  foreground.     In  the  case  of  Straiih  there  developed  within  two 


ADDISON  S    DISEASE  339 

weeks  asthenia,  adynamia,  pigmentations  that  were  iron-free,  and  only  a 
shght  depression  of  the  blood-pressure.  Also  psychic  disturbances  (at  first 
more  excitement,  then  apathy)  made  their  appearance.  Autopsy  showed 
a  scirrhous  carcinoma  of  the  pylorus  with  metastases  into  the  retroperitoneal 
tissue,  especially  at  the  hilus  of  the  left  kidney,  into  the  lungs  and  pleura,  and 
bilateral  thrombosis  of  the  suprarenal.  The  older  of  these  could  very  well 
have  occurred  simultaneous  with  the  beginning  of  the  Addison's  disease. 

Moreover,  sometimes  in  the  subacute  cases  there  is  observed  graded 
[schubweises]  occurrence  of  the  stormy  manifestations.  Chronic  Addi- 
son's disease  mostly  shows  remissions,  in  which  also  the  pigmentation  may 
retrogress.  Cases  that  have  lasted  ten  years  are  on  record.  As  the  remis- 
sions may  have  lasted  for  years,  we  must  be  cautious  as  to  our  assertions 
that  an  individual  case  has  been  cured. 

Such  individuals  with  chronic  Addison's  disease  are  for  the  most  part 
very  labile;  physical  exertion,  excitements  or  slight  complicating  affections 
may  lead  to  a  fatal  collapse. 

As  an  example  of  the  chronic  course,  I  cite  the  following  case: 

Observation  XLVI. — H.  K.,  forty-two  years.  Entered  the  clinic  Nov.,  191 1.  No 
tuberculous  taint;  the  family,  however,  shows  the  presence  of  gout.  The  illness  began 
ten  years  ago,  when  a  gradually  increasing  brown  coloration  of  the  skin  became  ap- 
parent; during  the  first  years  the  coloration  was  extraordinarily  intense,  the  greater  part 
of  the  skin,  but  especially  that  of  the  face,  the  neck,  hands  and  forearms  being  deep 
brown — a  bronze  color.  Since  that  time  the  brown  coloration  has  persisted  in  varying 
intensity.  At  that  time  the  patient  spent  a  year  at  Davos,  as  the  lungs  had  become 
affected.  Ten  years  ago  an  attack  of  articular  rheumatism  that  affected  especially  the 
joints  of  the  feet  and  toes.  Since  that  time  several  attacks,  two  or  three  times  a  year, 
in  which  the  most  different  joints  are  involved.  At  present  such  an  attack  is  in  prog- 
ress after  an  interval  of  some  years.     Loss  of  12  kg.  weight  during  the  last  half  year. 

On  examination,  it  was  found  that  the  skin  of  the  whole  body  shows  a  brown  colora- 
tion, which  is  especially  intense  on  the  extensor  surface  of  the  forearm,  on  the  backs  of 
the  hands,  on  the  face  and  neck,  and  on  the  genitalia  and  inguinal  region.  The  brown 
coloration  is  partly  diffuse,  partly  more  circumscribed  in  spots,  the  individual  spots  at- 
taining the  size  of  a  lentil.  Mucous  membranes  of  the  lips,  mouth,  and  throat  show 
numerous  mustard-seed-sized,  irregularly  limited  brownish-black  spots,  which  are  espe- 
cially distinct  on  the  mucous  membrane  of  the  cheeks.  The  mucous  membranes  are 
pale,  the  skin  is  dry,  the  percussion  sound  over  the  left  pulmonary  apex  is  shortened,  the 
vesicular  murmur  weakened;  no  rales.  The  cardiac  dulness  is  rather  small,  the  heart- 
sounds  are  clear,  the  blood-pressure,  according  to  Gartner,  60,  liver  and  spleen  not  enlarged. 

Several  joints  are  reddened,  swollen  and  painful,  especially  both  knee-joints,  right 
great  toe-joint,  left  ankle-joint,  left  shoulder-joint,  right  elbow-joint  and  left  hand-joint. 

No  uric  acid  demonstrable  in  blood. 

Traces  only  of  albumin  in  the  urine. 

Temperature  up  to  over  38°. 

Estimation  of  sugar  in  the  blood  {Bernstein)  0.067  P^r  cent. 

Leucocyte  count  normal  (8  per  cent,  eosinophiles).  We  are  here  dealing  with  the 
chronic  Addison's  disease,  that  has  existed  for  ten  years  and  that  shows  long  remissions. 
During  the  last  years  the  condition  is  apparently  rather  stationary,  lately  a  new  exacer- 


34°  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

bation  (reduction  in  weight).     With  this  there  exists    complications    with    frequently 
recurring  articular  rheumatism. 

Pathological  Anatomy .^ — Congenital  errors  of  development  of  the  supra- 
renal are  often  found  combined  with  other  malformations.  Zander  quotes 
forty-two  cases  of  hemicephaly  in  which  the  suprarenals  were  always  small. 
This  finding  is  also  constant  with  other  malformations,  if  there  is  an  absence  of 
the  anterior  cerebral  hemispheres.  There  apparently  exists  in  such  cases 
aplasia  of  the  cortical  system.  At  least  Elliott  and  Armour  in  a  case  of  anen- 
cephalus  found  the  suprarenal  medulla  and  the  paraganglia  normal,  while 
the  cortex  was  entirely  absent.  Czerny  found  the  medullary  substance 
entirely  absent  in  five  cases  of  congenital  hydrocephalus.  Ulrich  observed 
in  an  adult  complete  aplasia  of  the  suprarenal  medulla;  here  the  paraganglia 
must  have  been  especially  well  developed. 

Important  practically  is  the  hypoplasia  of  the  chromaffin  tissue  described 
by  Wiesel,  Hedinger,  Goldzieher,  and  others,  which  is  mostly  associated  with 
status  lymphaticus  and  sometimes  with  great  parenchymal  value  of  the 
thymus  gland.  According  to  Wiesel  such  individuals  are  especially  predis- 
posed to  Addison's  disease.  Acute  destruction  of  the  suprarenals  may  occur 
as  a  result  of  hemorrhage  of  thrombosis  of  the  suprarenal  veins  (Virchow, 
Carrington,  KarakascheJ,Goldzieher,  [Lavenson,  Ilektoen,  Ellis])  and  others  or 
through  suppuration  (Janowsky).  Much  more  frequent  are  simple  atrophy 
or  sclerosis  {RoloJ,  Simmonds,  Bittorf,  Goldzieher). 

Bittorf  collected  forty-seven  cases  of  true  atrophy  or  cirrhosis  of  the  supra- 
renal glands,  adding  to  these  three  cases  of  his  own.  In  such  cases  the  supra- 
renals are  much  decreased  in  size  or  entirely  shrunken  and  often  grown 
together  with  the  surrounding  tissue.  Microscopical  examination  usually 
shows  a  very  considerable  reduction  of  the  parenchyma,  fattening  and 
eventually  necrosis  of  the  cells.  With  the  cirrhosis,  one  finds  thickening 
or  obliteration  of  the  vessels,  and  growing  together  with  the  surround- 
ings. Sometimes  the  sclerosis  exists  on  a  luetic  basis  {Schwyzer,  Esser). 
Esser  found  gummata  in  connection  with  symptoms  resembling  Addison's 
disease  in  a  new-born.  According  to  Lichtwitz,  pigmentations  occur  in  all 
these  cases.  This  author  found  the  condition  complicated  with  scleroderma 
in  four  cases  in  the  literature,  adding  a  fifth  case.  Most  commonly,  how- 
ever, tuberculosis  of  the  suprarenals  is  found  bilateral,  not  rarely  isolated. 
Often,  however,  other  tuberculous  foci  in  the  body  are  found.  Among  five 
hundred  forty-nine  cases  from  the  literature,  Elsdsser  found  isolated  tuber- 
culosis of  the  suprarenals  in  17  per  cent.,  in  48  per  cent,  combination  with 
pulmonary  tuberculosis,  and  tuberculous  foci  in  other  parts  of  the  body  in 
the  rest  of  the  cases. 

In  four  hundred  seventy-two  cases  the  lesion  of  the  suprarenal  was  bi- 
lateral. The  suprarenals  may  be  destroyed  also  by  tumors.  Bittorf  re- 
ports two  cases  of  hypernephromata  with  symptoms  of  Addison's  disease. 


Addison's  disease  341 

There  are  also  cases  of  Addison's  disease  in  which  the  suprarenals  are 
found  to  be  healthy.  Nieszkowski,  and  Virchow,  first  reported  such  cases. 
Lewin  found  them  in  12  per  cent,  of  five  hundred  sixty-one  cases.  There  are, 
further,  cases  in  which  clinically  no  signs  of  Addison's  disease  are  present, 
but  at  autopsy  show  destruction  of  both  suprarenals.  v.  Neusser  hence 
expressed  the  thought  that  a  lesion  in  the  splanchnic  itself  or  at  some  other 
point  of  the  sympathetic  system  could  lead  to  Addison's  disease.  There  are 
but  few  cases,  however  {Jurgens,  Bramwell),  that  are  adapted  for  such  an 
explanation;  otherwise  changes  in  the  sympathetic  are  rare  and  mostly  slight 
{v.  Kahlden,  Martineau).  An  explanation  of  the  above-mentioned  exceptions 
would  be  possible  only  on  the  recognition  that  the  suprarenals  represent  only 
a  part  of  the  chromaffin  or  interrenal  system,  and  on  the  consideration  of  the 
presence  of  accessory  suprarenals. 

Whether  the  complete  or  partial  destruction  of  the  suprarenals  will  in  a 
given  case  lead  to  Addison's  disease,  depends  upon  the  fact  whether  the  por- 
tion of  the  suprarenal  apparatus  lying  outside  the  glands  proper  is  sufficiently 
well  developed  to  assume  the  function  of  the  destroyed  tissue,  apparently 
also  on  whether  the  destruction  has  progressed  slowly  enough  to  give  time 
for  vicarious  hypertrophy. 

There  has  taken  place  a  lively  discussion  as  to  whether  Addison's  disease 
should  be  referred  to  a  lesion  of  the  chromaffin  tissue  or  the  interrenal  system. 
Wiesel  in  five  cases  of  Addison's  disease  observed  that  the  entire  chromaf&n 
tissue  was  destroyed,  while  the  cortex  seemed  to  be  less  affected.  He  thought 
that  the  destructive  process  began  primarily  in  the  chromaffin  tissue,  and 
involved  the  cortex  only  secondarily.  On  the  other  hand,  Karakaschef 
reported  cases  in  which  chiefly  the  cortex  was  affected,  and  in  which  he 
regarded  the  cortical  lesion  as  the  sole  course  of  the  symptom-complex.  The 
question  is  not  as  yet  fully  cleared  up,  although  the  pathologico-anatomical 
investigations  of  latter  times  and  the  physiological  researches  tend  to  show 
that  in  Addison's  disease  a  disturbance  of  function  of  both  suprarenal  systems 
is  present,  a  standpoint  that  is  upheld  in  the  new  monographs  {Bittorf, 
V.  Neusser  and  Wiesel,  Biedl).  Of  other  pathologico-anatomical  findings  I 
mention  only  the  known  atrophy  of  the  heart,  and  the  atrophy  of  the 
sexual  glands  that  is  almost  regularly  present.  Kyrle  has  made  exact  in- 
vestigations as  to  the  testicles.  He  found  a  deficient  spermatogenesis  and 
also  changes  in  the  interstitial  glands. 

It  is  very  noteworthy  that  the  suprarenal  often  becomes  affected  espe- 
cially in  severely  infectious  diseases  and  intoxications.  Diphtheria  toxin  has 
an  especial  affinity  for  the  suprarenals.  In  animals  after  the  injection  of 
diphtheria  toxin,  the  suprarenals  are  always  found  to  be  markedly  hyperemic 
and  suffused  with  hemorrhages  (Roux  and  Yersin) .  Necroses,  hemorrhages, 
and  edema  of  the  suprarenals  are  found  in  the  various  infectious  diseases 
{Oppenheim  and  Loeper).     In  many  cases,  an  acute  insufficiency  of  the  supra- 


342  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

renal  apparatus  and  especially  the  chromafiEin  tissue  is  well  an  important  cause 
of  the  cardiac  insufficiency.  In  such  cases  the  suprarenals  show  an  essential 
reduction  in  their  adrenalin  content  {Comessati,  Schmorl,  Goldzieher) . 

Finally  wx  must  mention  a  rare  finding  of  v.  Recklinghausen^ s .  In  an 
eighteen-year-old  dwarf  wdio  died  in  convulsions,  he  found  what  was  apparently 
a  very  chronic  tuberculous  change  of  both  suprarenals.  I  shall  have  occasion 
to  refer  to  this  case  later. 

Pathological  Physiology  of  the  Suprarenals.— The  thesis  established  by 
Broicn-Scquard  that  the  extirpation  of  both  suprarenals  led  to  the  death  of 
the  animal  experimented  on  has  met  with  much  contradiction.  The  sure 
knowledge  that  the  cortical  system  and  chromaffin  tissue  are  in  like  manner 
important  for  life  was  first  mentioned  by  later  investigators  (I  mention  only 
Biedl,  Hultgren,  and  Anderson)  who  took  into  consideration  the  presence  of 
accessory  suprarenals. 

Biedl  could  at  the  same  time  furnish  important  demonstration  that  the 
death  of  the  animal  was  not  to  be  blamed  on  the  operative  shock  due  to 
injury  of  the  sympathetic  nerve  plexus,  as  the  operation  also  ended  fatally 
after  transplantation  of  the  suprarenals  under  the  skin.  After  extirpation 
of  both  suprarenals,  the  animals,  after  a  latent  period,  showed  increasing 
apathy,  adynamia,  paresis,  and  emaciation.  Blood-pressure  and  bodily 
temperature  gradually  sank,  so  did  also  the  amount  of  blood  sugar  (Forges, 
Bierri,  and  Malloisel).  Injection  of  phloridzin  would  now  produce  no 
glycosuria  or  only  minimal  glycosuria  (Eppinger,  Falta,  and  Riidinger) ;  the 
glycogen  rapidly  disappeared  from  the  liver  and  muscles  (Forges),  there 
existed  a  higher  sensitivity  for  poisons  (O.  Schwarz) ,  the  blood  seemed  to  act 
toxic,  death  occurring  in  convulsions.  The  symptom  picture  shows  great 
similarity  with  the  peracute  case  of  Addison's  disease.  We  have  not  as 
yet  a  sufficient  explanation  as  to  the  question  as  to  which  symptoms  of 
Addison's  disease  are  to  be  referred  to  the  absence  of  the  medullary  system 
and  which  to  that  of  the  cortical  system.  Before  I  enter  into  this  question, 
I  will  briefly  mention  the  most  important  facts  we  know  as  to  the  physio- 
logical significance  of  these  systems. 

The  active  constituent  of  the  chromaffin  tissue  is  adrenalin.  After  the 
important  preliminary  researches  of  v.  Furth,  it  was  first  isolated  in  a  crystal- 
line form  by  Takamine  and  Aldric/i. 

Later  investigations  of  Aldrich,  v.  Furth,  Pauli,  et  al.,  then  led  to  the 
establishment  of  its  chemical  formula.  It  is  a  methylaminoethanol  pyro- 
catechin,  with  the  formula  C9H13NO3. 

Stolz  first  succeeded  in  making  optically  inactive  adrenalin  synthetically, 
and  Fldcher  then  obtained  the  separation  into  the  dextro-  and  sinistro- 
adrenalins.  The  sinistro-adrenalin  is  far  the  more  active  and  is  identical 
with  that  produced  in  the  body  (Abderhalden) .     Probably  the  organism 


ADDISON  S    DISEASE  343 

forms  adrenalin  from  the  aromatic  split  products  of  albumin,  tyrosin,  and 
phenylalanin  or  oxyphenylserin  {Halle,  Frdnkel,  Friedmann) . 

Of  the  chemical  methods  for  demonstrating  adrenalin  we  will  mention 
only  the  iron  chloride  test  (Vulpian),  the  sublimate  test  (Comesatti),  the 
iodine  reaction  {Vulpian,  Schur,  Frdnkel,  and  Allers),  the  potassium  perman- 
ganate lactic  acid  test  {Zanfrognini) . 

I  shall  limit  m.yself  to  sketching  briefly  the  most  important  of  adrenalin's 
physiological  actions.  It  acts  as  a  powerful  increaser  of  the  blood-pressure 
through  narrowing  of  the  peripheral  vessels,  it  mostly  acts  first  by  slowing 
the  pulse,  then  accelerating  the  pulse;  it  slows  the  pulse  by  reflex  excitation 
of  the  vagus  center,  this  action  belonging  to  the  so-called  by-activities 
[Nebeneinwirkungen]  of  adrenalin  (Biedl).  Other  by-activities  are  the  shal- 
lowing of  respiration,  and,  according  to  Biedl  perhaps  also  the  increase  of 
the  excitabiUty  of  the  striated  muscles.  It  acts  in  a  relaxing  manner  on  the 
stomach  and  intestines,  as  a  contracting  agent  on  the  three  sphincters  (the 
pyloric,  and  ileo-colic,  and  the  internal  sphincter  of  the  anus) .  The  uterine 
muscle  is  contracted  or  relaxed  by  adrenalin,  according  to  whether  the 
pressor  [fordernden]  or  the  inhibitory  fibers  predominate  or  are  excitable 
(Falta  and  Fleming).  Probably  the  bladder  behaves  in  the  same  manner. 
Under  circumstances  mydriasis  occurs.  The  vessels  of  the  kidneys  react  to 
minimal  doses  by  dilatation  and  diuresis  iJonescu).  Under  circumstances 
adrenalin  may  produce  salivation  and  secretion  of  tears,  indeed  in  large 
doses  (in  guinea-pigs) ,  also  secretion  of  sweat  {Falta  and  Ivcovic) .  Adrenalin 
produces  hyperglycemia  and  glycosuria  {F.  Blum,  Metzger,  and  ZiiUzer) .  The 
hyperglycemia  comes  about  by  mobilization  of  the  glycogen  and  probably 
also  by  secondarily  increased  carbohydrate  formation  in  the  liver  {Eppinger, 
Falta,  and  Rudinger,  L.  Pollak).  It  increases  the  protein  decomposition 
during  hunger.  At  the  same  time  the  respiratory  quotient  is  temporarily 
increased  {Bernstein  and  Falta).  In  large  doses  it  produces  in  dogs  increased 
elimination  of  uric  acid  and  allantoin.  Often  it  leads  to  increase  of  tem- 
perature. Further  it  brings  about  a  neutrophilic  hyperleucocytosis,  during 
which  the  eosinophiles  vanish  from  the  circulating  blood.  The  simultaneous 
increase  of  the  mononuclear  cells  is  a  by-action,  as  this  remains  absent 
after  the  administration  of  atropine.  Finally  adrenalin  produces  hyper- 
globulia  {Bertelli,  Falta.  and  Schweeger),  chiefly  through  transudation  of 
plasma. 

Apart  from  the  accessory  actions  mentioned,  adrenalin  acts  only  on  the 
purely  sympathetic  nerve-endings,  and  indeed  on  the  so-called  musculo- 
neural  junction  {Langley,  Elliott).  It  is  therefore  a  pureh^  sympathetic 
hormone.  The  giving-ofl'  of  adrenahn  to  the  blood  of  the  vena  cava  is  con- 
tinuous. The  blood  of  the  suprarenal  vein  should  contain  about  one-half 
part  per  million  of  adrenalin  per  cc.  {Ehrmann).  Biedl  estimates  that  in 
twenty-four  hours  about  4.3  mg.  are  given  oft"  to  the  blood.     This  amount 


344  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

of  adrenalin  may  be  increased  by  stimulation  of  the  suprarenal  nerves  [Biedl, 
A  slier). 

The  assumption  that  the  activity  of  the  chromaffin  tissue  and  the  excita- 
bility of  the  myoneural  junction  (Bayliss  and  Starling)  is  regulated  by  cen- 
ters lying  in  the  medulla  oblongata  is  essentially  based  on  the  knowledge 
that  "puncture  glycosuria"  is  brought  about  by  dissemination  of  adrenalin 
by  means  of  the  chromaffin  tissue.  Already  Blum  had  supposed  this.  Ep- 
pinger,  Falta,  and  Rudinger  further  pointed  out  concerning  this  that  in  the  dog 
without  a  thyroid,  "piqure"  may  remain  as  ineffective  as  injection  of  adrena- 
lin. After  A .  Mayer  had  established  the  fact  that "  piqure  "  remains  ineffect- 
ive in  rabbits  after  bilateral  removal  of  the  suprarenals,  Waterman  and 
Smith  tried  to  demonstrate  an  adrenalinemia  by  means  of  the  insufficient 
Ehrmann  s  reaction.  The  question  was  first  entirely  cleared  up  by  the  inves- 
tigations of  R.  Kahn.  This  author  could  show  that  after  the  sugar-puncture, 
the  tingibiHty  of  the  suprarenals  to  chrome  stains  in  great  part  disappears 
and  the  contents  of  adrenalin  markedly  diminish.  Cutting  of  the  splanch- 
nic nerves  not  only  prevents  the  occurrence  of  "piqure"  glycosuria,  as  Claude 
Bernard  had  shown,  but  also  the  coming  about  of  any  change  in  the  suprarenal 
medulla.  It  should  be  noted  that  in  rabbits  the  right  suprarenal  is  supplied 
by  the  right  and  left  splanchnic,  the  left  by  the  right  splanchnic  only. 

We  will  now  consider  the  path  that  adrenalin  takes  in  the  body.  The 
blood  in  the  cava,  containing  the  adrenalin,  first  reaches  the  right  heart  and 
then  the  lungs.  The  pulmonary  vessels  act  refractory  to  it;  hardly  any 
adrenalin  is  consumed  here  (Brodie  and  Dixon) .  From  the  lungs  it  reaches 
the  left  heart  and  from  this  the  greater  circulation.  The  coronary  vessels 
of  both  sides  of  the  heart  are  dilated  by  it,  hence  the  heart  is  better  permeated 
with  blood  {Langendorf).  That  part  of  the  adrenalin-containing  blood  which 
flows  through  the  brain,  also  hardly  loses  in  its  adrenahn  contents;  the 
cerebral  vessels  are  dilated  (Gerhardt) .  On  the  contrary  there  occurs  a  marked 
consumption  of  adrenalin  in  the  other  peripheral  capillary  territories  of  the 
body,  especially  the  muscles  and  the  intestines  {Elliott,  Carnot  and  Josser  and, 
Falta  and  Priestly).  It  therefore  is  to  be  assumed  that  the  blood  proceeding 
from  these  organs  (veins  of  the  extremities,  portal  veins)  is  adrenalin-free 
or  at  least  poor  in  adrenalin.  Therefore  it  is  very  striking  that  the  test  of  the 
arterial  and  venous  blood  as  to  its  adrenalin  contents  by  means  of  the  known 
biological  methods  (frog  eyes,  strips  of  vessel,  uterus  method)  in  the  experi- 
ment of  Falta  and  Fleming  showed  just  as  strong  an  action,  if  indeed  not 
stronger,  of  the  venous  blood  (extremity).  On  the  contrary,  after  the  subcu- 
taneous injection  of  adrenalin,  the  arterial  blood  showed  stronger  action. 
We  must  therefore  be  very  cautious  in  the  interpretation  of  the  biological 
methods  mentioned,  as  the  pressor  action  of  the  blood  serum  must  depend 
on  other,  as  yet  unknown,  factors,  a  view  that  is  also  upheld  by  O'Connor. 
I  shall  have  something  to  say  later  as  to  the  value  of  the  biological  methods 


ADDISON  S    DISEASE  345 

that  we  use  for  demonstrating  adrenalin  in  the  blood  serum.  However  this 
may  be,  a  stronger  unloading  of  the  chromaffin  tissue  must  lead  to  a  quite 
definite  distribution  of  blood.  We  find  slight  hyperemia  of  the  lungs,  the 
heart,  the  brain,  the  kidneys,  marked  hyperemia  of  the  peripheral  venous 
system  and  above  all  that  of  the  liver  and  the  roots  of  the  portal  vein,  while 
the  other  capillary  systems  are  poor  in  blood.  The  purpose  of  this  arrange- 
ment is  evident.  It  means  the  forcing  of  a  greater  amount  of  blood  into 
those  organs  which  are  the  seat  of  life-maintaining  centers  and  of  the  regula- 
tion of  metabohsm,  thus  heightening  the  activity  of  these  organs.  The  hver 
occupies  an  especial  position:  It  receives  adrenalin-poor  or  adrenahn-free 
blood  through  the  portal  vein  and  thus  becomes  markedly  hyperemic,  and 
blood  containing  adrenalin  through  the  hepatic  arteries;  by  this  means 
especially  favorable  conditions  are,  it  seems,  provided  for  the  action  of 
adrenalin  on  the  metabolism  (Falta  and  Priestley).  Also  £.  Neubauer  found 
by  oncometric  methods  a  hyperemia  of  the  liver  after  the  injection  of 
adrenalin. 

The  physiological  significance  of  the  chromaffin  tissue  may  be  adduced 
from  what  has  just  been  said  with  regard  to  adrenalin's  intensive  and  mani- 
fold actions.  We  may  assume  that  it  maintains  the  normal  excitability 
of  the  sympathetic  nerves  and  that  by  means  of  graduation  of  the  secretion 
it  is  concerned  in  the  regulation  of  the  blood-pressure,  the  distribution  of 
blood,  and  the  tonus  of  all  other  organs  innervated  by  the  sympathetic;  fur- 
ther that  it  maintains  constant  the  amount  of  sugar  in  the  blood  and  enters  in 
a  regulatory  manner  into  other  factors  of  the  metabolism ;  further  that  it 
influences  muscular  power  (whether  directly  or  through  carbohydrate  meta- 
bolism is  questionable) ;  and  finally  it  exercises  an  influence  on  the  production 
of  neutrophilic  leucocytes  and  on  the  plasma  contents  of  the  circulating  blood. 

As  to  the  function  of  the  cortical  system,  we  as  yet  know  very  little.  Ac- 
cording to  Jacoby,  it  contains  an  oxydase.  Lohmann  obtained  choHn  from 
the  cortex.  Cholin  acts  as  a  toning  agent  on  the  autonomous  nerves  and  it 
is  also  found,  however,  in  many  other  organs,  and  we  do  not  know  whether 
it  is  given  off  from  the  cortical  system  in  the  blood  paths.  The  assumption 
of  a  "systeme  cholinogene"  (Gautrelet)  as  an  antagonistic  regulator  against 
the  chromaffin  system  has  not  as  yet  received  sufficient  support.  Also  the 
experiments  of  Goldzieher  do  not  seem  to  me  conclusive  enough  with  respect 
to  the  significance  of  this  question. 

It  is  assumed  rather  generally  that  the  cortical  system  possesses  a  detoxi- 
cating  function  (Brown-Sequard).  The  blood  of  animals  without  their  supra- 
renals  seems  to  be  poisonous.  As  has  been  mentioned  previously  these 
animals  show  a  greater  susceptibility  for  certain  poisons;  this  does  not,  how- 
ever, furnish  absolute  evidence  for  the  detoxicating  activity  of  the  supra- 
renals,  as  we  may  assume  with  Theiroloix  that  the  withdrawal  of  the  regula- 
tory function  lessens  the  general  resistance.     It  is  supposed  by  many  authors 


346  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

that  the  symptoms  on  the  part  of  the  intestinal  tract  and  the  central  nervous 
system,  which  are  severe  and  remind  one  of  an  acute  poisoning,  depend  on  the 
falUng  out  of  the  function  of  the  cortex.  It  should  further  be  mentioned 
that  in  the  growing  organism  enormous  influences  on  sexual  glands  and  the 
general  hairiness  proceed  from  the  cortical  system.  I  shall  return  to  these 
in  detail  later. 

Pathogenesis  of  Addison's  Disease. — Also  the  results  of  the  pathologico- 
physiological  investigations  just  cited  justify  the  dictumthat  Addison^ s disease 
depends  on  an  acute  or  chronic  more  or  less  complete  loss  of  the  Junction  of  the 
suprarenal  apparatus. 

Probably  from  youth  up  there  exists  in  individuals  who  acquire  an  Addi- 
son's disease  a  certain  weakness  of  the  suprarenal  function  {Wiesel).  Almost 
always  we  find  pathological  processes  which  have  affected  the  suprarenal 
apparatus  itself,  but  we  cannot  on  this  account  rule  out  the  assumption  that 
an  affection  of  the  nervous  apparatus  regulating  the  activity  of  the  suprarenal 
apparatus  cannot  lead  to  a  (after  a  fashion)  purely  functional  Addison's 
disease. 

Very  difhcult  is  the  comprehension  of  the  rare  cases  of  Addison's  disease 
with  unilateral  affection  of  the  suprarenal  apparatus  that  become  healed 
after  extirpation  of  the  affected  suprarenal,  v.  Neusser  has  supposed  a 
reflex  influencing  of  the  healthy  suprarenal  after  the  manner  of  reflex  anuria, 
and  Bittorf  a  damaging  of  the  same  through  abnormal  metabolic  products  of 
the  diseased  gland. 

Among  the  symptoms  of  Addison's  disease  depending  on  the  lessening 
of  function  of  the  chromafiin  tissue  probably  are  the  low  blood-pressure,  the 
low  sugar  contents  of  the  blood,  the  abnormally  high  tolerance  for  grape- 
sugar,  the  adynamia,  and  the  mononucleosis  or  the  status  lymphaticus, 
although  in  the  explanation  of  the  alterations  in  the  hematopoietic  apparatus 
we  must  not  forget  what  is  frequently  present — tuberculosis.  To  the  defi- 
ciency of  the  cortical  system  are  referred  by  most  authors  the  manifestations 
on  the  part  of  the  gastrointestinal  tract,  vomiting,  diarrheas,  etc.,  and  the 
psychical  alterations,  the  convulsions,  delirium,  coma,  etc.  No  certain  justi- 
fication for  these  views  have  as  yet  been  adduced  (see  later). 

Very  difflcult  is  the  interpretation  of  the  coming  into  existence  of  the 
pigmentations  in  Addison's  disease.  The  pigment  is  always  iron-free. 
On  reduction  with  hydriodic  acid  it  yields  no  hemopyrrol  and  on  oxidation 
no  hematinic  acid.  We  have,  therefore,  discarded  any  relationship  with 
blood  pigment,  and  have  found  the  mother  substances  in  the  aromatic  split 
products  of  albumin  (tryptophan,  tyrosin,  and  also  adrenalin)  (5.  Frdnkel). 
Further,  Ziizer  and  Lichtwitz  saw  the  occurrence  of  pigmentation  of  the 
skin  and  mucous  membranes  after  the  injection  of  adrenalin  in  rabbits.  As 
according  to  Eppinger  the  melanogen  in  melanocarcinoma  is  an  N-methy- 
pyrrolidinoxycarbonic   acid   and   its   elimination   is   increased   through   the 


ADDISOX  S    DISEASE  347 

administration  of  tr^-ptophan,  so  it  would  not  be  unlikely  that  an  increased 
production  of  tryptophan  has  been  brought  about  in  the  body  by  the  ad- 
ministration of  adrenalin.  Further  it  should  be  mentioned  that  Xeuherg 
demonstrated  in  the  tumors  of  the  cases  of  melanoma  of  the  suprarenal 
cortex  a  ferment  which  let  a  pigment  formation  be  recognized  after  the  addi- 
tion of  adrenalin  or  ox}'phenylethylamin.  Further  Jaeger  has  obtained 
from  a  melanoma  an  enzyme  that  decomposes  adrenalin  with  pigment  forma- 
tion. Jaeger  supposes  that  adrenalin  is  the  mother  substance  of  the  iron-free 
pigment  of  the  organism.  Finally,  according  to  Meiroicsky.  freshly  excised 
pieces  of  skin  show  in  the  incubator  an  increase  of  pigmentation,  and  accord- 
ing to  Kdnigstein  this  increase  of  pigment  is  greater  in  the  skin  of  dogs  without 
their  suprarenals.  Therefore  it  would  not  be  unhkely  that  the  cortex  as  well 
as  the  chromaffin  takes  part  in  the  pigment  formation,  the  first  furnishing  the 
mother  substance  of  the  melanogen  (tr}-ptophan),  the  latter  the  further  de- 
composition. Increased  formation  of  pigment  may  occur  under  the  most 
diverse  circumstances,  as  in  Basedow's  disease,  when  the  production  of  ad- 
renalin is  increased,  or  in  Addison's  disease  when  the  production  of  adrenahn 
is  absolutely  lessened,  or  perhaps  less  disturbed  than  the  function  of  the  corti- 
cal system.  Thus  may  also  be  seen  why  pigment  formation  often  remains 
away  entirely  in  acute  destruction  of  the  entire  suprarenal  apparatus.  This 
should,  however,  be  regarded  merely  as  a  hypothesis  that  still  requires 
experimental  support. 

Differential  Diagnosis. — For  differential  diagnosis,  of  great  importance 
are  the  pigmentations.  The  number  of  cases  of  Addison's  disease  without 
melanoderma  is,  as  Bittorf  has  emphasized,  less  than  the  older  statistics 
would  lead  one  to  expect.  Similar  pigmentations  are  found,  however,  in 
normal  individuals.  Also  in  itching  skin  affections  and  [those  due]  to  ver- 
min, during  the  use  of  arsenic,  in  pregnancy,  in  chronic  heart  affections  and  in 
phthisis  pulmonahs;  in  sKght  grades  of  the  latter  the  thought  of  Addison's 
disease  may  be  erroneously  awakened  on  account  of  the  emaciation  and  the 
slighter  h}'potonia;  it  is  hence  important  to  remember  that  in  all  conditions 
enumerated  the  mucous  membranes  remain  free.  In  persons  cachectically 
tuberculous  the  pigmentations  may  become  quite  similar  to  those  of  Addison's 
disease.  Here  indeed  it  is  questionable  whether  the  pigmentations  might 
not  be  referred  directly  to  a  damaging  of  the  suprarenal  function,  an  opinion 
that  is  upheld  by  Lavignel-Lai^astine. 

In  cirrhose  bronzee  the  coloration  of  the  skin  is  more  blue-gray;  here  also. 
the  mucous  membranes  are  affected  only  rarely  and  more  in  a  diffuse  form 
{Heller).  Here  we  should  consider  the  liver  lesion  and  the  eventual  compli- 
cation with  pancreatic  disease  (diabetes).  Naturally  it  should  be  taken  into 
consideration  that  combinations  of  cirrhose  bronzee  and  Addison's  disease 
may  occur,  if  the  sclerosing  process  in  cirrhose  bronzee  also  involves  in  strong 
degree  the  suprarenal  apparatus  (Fod,  Bittorf).     As  is  known,  pigmentations 


348  THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

are  also  frequent  in  scleroderma.  From  this  we  must  not  conclude  that  a 
complication  of  scleroderma  with  Addison's  disease  is  present  in  the  indi- 
vidual cases  as  pigmentations  belong  to  scleroderma  as  such.  Also  similar 
pigmentations  are  observed  in  pellagra  (v.  Xeusser).  Statements  as  to  the 
characteristic  erythema  in  the  warm  seasons  of  the  year  clinch  the  diagnosis 
in  this  case.  Arsenic  melanosis  and  argyrosis  show  another  tint.  Pigmen- 
tations are  also  observed  in  leucemia.  v.  Xeusser  thought  that  there  were 
leucemic  infiltrations  of  the  suprarenals,  which  opinion  a  case  of  Zeigler's 
later  corroborated.  Pigmentations  in  Basedow's  disease  are  very  common. 
The  complication  with  Addison's  disease  is  very  rare.  However,  such 
cases  in  which  the  diagnosis  was  confirmed  by  autopsy  have  been  reported 
by  Fletcher,  and  by  GreenJiou'.  Such  a  diagnosis  should  be  made  in  vivo  with 
great  caution,  as  markedly  pigmented  cases  of  Basedow's  disease  with 
cachectic  symptoms — such  as  occur  in  the  latter  stages — can  easily  give  rise 
to  the  impression  of  a  concomitant  Addison's  disease. 

Very  diflicult  is  the  delimitation  from  cachectic  conditions  associated  with 
occult  carcinomas  and  diseases  of  the  liver,  in  which  diseases  melanoplakia 
of  the  oral  mucous  membrane  may  occur  also  (ScJmltze).  In  these  cases  and 
in  the  case  of  Addisonoid  anemias  described  by  Grauitz,  the  demonstration 
of  a  hj'poglycemia  and  of  a  mononucleosis  with  h}'pereosinophilia  is  very 
important. 

The  diagnosis  of  acute  Addison's  disease  may  be  very  difficult.  Brodnitz 
points  out  the  importance  of  the  following  syndrome:  Extraordinary  slow- 
ing of  the  fully  tense  pulse  with  normal  temperature;  violent  intestinal  colics 
occurring  in  attacks;  failure  of  the  peristalsis  and  isolated  intestinal  disten- 
tion. Brodnitz  beheves  that  thrombosis  of  the  suprarenal  vein  occurs  in 
many  cases  of  postoperative  spastic  occlusion  of  the  intestine. 

The  prognosis  of  Addison's  disease  is  always  very  dubious.  The  few 
certain  cases  of  cure  concern  mostly  luetic  disease  of  the  suprarenal,  some 
with  and  some  without  specific  treatment  {Merckel  and  Birch-HirscJifeld) ; 
in  a  case  of  Oesterreicll s  the  extirpation  of  the  one  tuberculous  suprarenal  led 
to  cure.  Cure  has  also  been  observed  in  cases  of  hypernephroma  with 
Addisonian  manifestations  (Bittorf). 

Treatment. — It  remains  to  be  said  that  treatment  is  very  ineftective. 
The  statements  as  to  improvement  after  subcutaneous  or  peroral  adminis- 
tration of  suprarenal  substance  are  more  sparse  than  those  concerning  results 
that  are  negative.  The  administration  of  small  doses  of  adrenalin  per  os  is 
inefi'ective.  as  might  be  gathered  from  our  researches,  which  show  that  even 
more  than  20  mg.  per  day  do  not  call  forth  any  especial  manifestations. 
Only  when  the  doses  are  very  much  larger  did  we  see  in  animals  after  admin- 
istration for  days  the  occurrence  of  hyperglycemia  {Falta  and  Turin).  I 
quote  one  of  our  experiments: 


ADDISON  S    DISEASE  349 

8.3  kg.  dog,  Mar.  5,  sugar  in  blood  0.1008  per  cent. 

On  March  8,  the  dog  received  daily  25  cc.  of  a  i  per  cent,  solution  of  adrenalin 
through  the  stomach  tube. 

From  March  9  to  16,  inclusive,  25  cc.  adrenalin  twice. 

Mar.  16,  sugar  in  blood,  0.1552  per  cent. 

From  Mar.  19  to  30,  inclusive,  25  cm.  adrenalin  twice. 

From  Mar.  13  to  17,  a  trace  of  sugar  was  demonstrable  in  urine,  later  the  urine  was 
always  sugar-free,  but  contained  traces  of  protein. 

Subcutaneous  injection  of  adrenalin  is  not  advisable  for  any  length  of 
time.  Boinet  saw  manifestations  of  collapse.  Also  after  the  injection  of 
the  glycerine  extract  of  the  whole  suprarenal  there  occurred  in  Boinefs  case, 
after  a  time,  conditions  of  excitement,  tremor,  and  insomnia.  Perhaps, 
however,  a  slight  result  is  to  be  obtained  by  the  peroral  administration  of 
tablets  made  from  the  whole  gland.  According  to  Magnus-Levy,  the  pigmen- 
tations have  become  lighter  in  color  after  the  administration  of  these 
tablets,  under  certain  circumstances. 

The  beautiful  investigations  of  v.  Haberer  and  Stoerck  as  to  the  healing-in 
of  pedunculated  suprarenal  glands  [transplanted]  into  the  kidney  scarcely 
give  hopes  for  a  practical  application,  as  apart  from  the  necessary  peduncula- 
tion,  probably  only  autotransplantations  of  the  suprarenals  are  possible. 

Only  the  symptomatological  treatment  remains.  Grawitz  recommends 
washing  the  stomach  with  sodium  chloride  solution,  predomination  of  vege- 
tative diet,  avoidance  of  alcohol,  and  hydrochloric  acid  medication.  Grawitz 
saw  a  case  that  presented  all  the  symptoms  of  Addison's  disease  which 
benefited  under  this  treatment.  Also  the  pigmentations  of  the  skin  disap- 
peared. The  case  was  observed  for  a  period  of  three  years  after  this  success- 
ful result.  Very  important  in  Addison's  disease  is  the  avoidance  of  every 
severe  exertion.  Boinet  reports  seven  cases  of  sudden  death  in  Addison's 
disease,  immediately  after  a  marked  fatigue. 

Proceeding  from  the  observation  that  dogs  after  the  extirpation  of  their 
suprarenals,  lose  all  their  glycogen  except  traces,  O.  Forges  combated  the 
adynamia  in  several  cases  of  Addison's  disease  by  the  administration  of 
large  amounts  of  carbohydrates  (especially  of  levulose)  with  good  results. 
Also  Gaiitrelet  reports  favorable  results. 

Here  might  also  be  mentioned  the  favorable  results  of  adrenalin  in  other 
diseases.  Very  widespread  is  the  employment  of  adrenalin  in  the  stilling  of 
hemorrhage.  Proceeding  from  the  observation  that  animals  bear  enormous 
amounts  of  adrenalin,  Turin  and  /  in  ulcus  ventriculi  increased  administra- 
tion of  adrenalin  per  os  up  to  7  mg.,  thrice  daily,  and  up  to  the  present  have 
seen  good  results.  Many  authors  report  the  excellent  action  of  adrenalin  in 
condition  of  collapse  {John  and  others),  especially  in  the  infectious  diseases 
(for  example,  Heubner,  in  diphtheria).  According  to  our  observations 
adrenalin  given  subcutaneously,  too,  in  man  increases  the  blood-pressure, 


350  THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

often  for  a  long  time.  According  to  our  experiment  the  subcutaneous  in- 
jection is  to  be  preferred  in  not  too  urgent  cases. 

Several  times  we  saw,  too,  an  astonishing  result  from  subcutaneous  admin- 
istration (thrice  5  mg.,  each  in  one-fourth  glass  of  water)  in  obstructing  car- 
cinoma of  the  esophagus,  in  which  the  passage  was  reestablished  probably  by 
subsidence  of  the  tumefaction  of  the  inflamed  mucous  membrane,  but  such 
results  only  last  for  a  few  days.  Further,  adrenalin  was  introduced  by  Neu 
into  obstetrical  practice.  After  the  injection  of  adrenalin  the  uterus  was 
brought  to  a  condition  of  tetanoid  contraction.  The  drug  has  been  especially 
serviceable  in  Cesarean  section.  It  may  be  injected  either  subcutaneously 
or  directly  into  the  uterus.  Probably  pituitrin  \d\\  supplant  adrenalin  in  this 
respect,  as  it  has  the  same  action  and  is  less  deleterious. 

The  employment  of  adrenalin  is  also  useful  in  phosphorus  poisoning.  E. 
Neubaner  and  Forges  observed  that  in  animals  poisoned  with  phosphorus, 
the  stainability  of  the  chromaffin  tissue  to  chromic  acid  disappeared;  both 
these  authors  attribute  the  vanishing  of  carbohydrates  from  the  liver,  the 
subsequent  fattening  of  the  liver  and  the  hypoglycemia  {E.  Xeuhauer,  and 
Frank  and  Isaac)  to  the  falhng  out  of  the  chromaffin  tissue  and  in  most  cases 
could  actually  prevent  these  symptoms  by  the  administration  of  adrenalin. 

As  to  the  treatment  of  osteomalacia  with  adrenalin,  sec  chapter  on  sexual 
glands  (appendix). 

2.  Isolated  Symptoms  due  to  Failure  of  Function  of  the 
Suprarenal  Cortex 

In  the  consideration  of  the  pathogenesis  of  Addison's  disease,  it  has  been 
pointed  out  that  we  as  yet  know  nothing  certain  concerning  that  group  of 
cases  which  has  as  the  basis  of  the  symptom-complex  the  destruction  of  the 
suprarenal  cortex.  It  is  true  that  many  authors  regard  the  manifestations  of 
intoxication  that  tend  to  enter  into  acute  cases  and  in  the  terminal  stages  of 
Addison's  disease  as  due  to  deficiency  or  absence  of  the  suprarenal  cortex. 
But  as  yet  experimental  pathology  has  furnished  no  certain  foundation  for 
this  assumption.  Nor  does  clinical  observation,  as  will  be  seen  from  the  fol- 
lowing, seem  to  me  to  substantiate  this  assumption. 

First  let  us  consider  the  malformations.  In  anencephalus  is  found,  as 
has  already  been  mentioned,  in  addition  to  anomalies  in  the  genital  organs, 
also  aplasia  of  the  suprarenals.  A  pert  points  out  that  in  aplasia  of  the  supra- 
renals  the  cortical  defect  seems  to  play  the  most  important  role.  I  mention 
again  the  case  of  anencephalus  reported  by  Elliott  and  Armour,  in  which  the 
suprarenal  medulla  and  the  paraganglia  were  intact.  Again,  in  cases  in  which 
the  suprarenals  are  entirely  absent  the  paraganglia  may  be  normal,  as  in  the 
case  oiApert.  The  aplasia  of  the  cortex  in  the  new-born  is  the  more  remark- 
able because  here  the  suprarenals,  as  is  known,  are  especially  well  developed. 


ISOLATED    SYMPTOMS    DUE    TO    SUPRARENAL    CORTICAL    FAILURE         35 1 

An  indication  as  to  the  direction  in  which  are  to  be  found  manifestations 
of  deficiency  of  the  suprarenal  cortex  is  found,  under  certain  circumstances, 
in  adenomata  of  the  suprarenal  cortex.  We  shall  see  later  that  in  such, 
hyperplasia  of  the  cortex  there  occurs  in  youth,  abnormally  rapid  growth  of 
the  organism  and  premature  development  of  the  secondary  sexual  characters 
and  the  genitalia,  and  in  adults  a  tendency  to  abnormal  hairiness.  Hence 
arises  the  thought  that  when  manifestations  of  the  opposite  kind  are  present 
there  may  exist  a  cortical  insufficiency. 

Moreover,  in  the  chapter  on  the  hypophysis  I  have  reported  a  case  of 
hypophysial  dystrophy  in  which  the  disease  first  developed  in  later  life  and  led 
to  a  marked  retrogression  of  the  hairiness  on  the  trunk  and  on  the  face.  In 
this  case  both  suprarenals  were  found  to  be  highly  sclerosed  and  we  shall  see 
later  in  the  consideration  of  the  multiple  ductless  glandular  sclerosis  that  in 
man  a  retrogression  of  the  secondary  sexual  characters  may  indeed  set  in  as 
the  result  of  the  failure  of  the  function  of  the  sexual  glands,  but  that  in 
woman  the  mere  loss  of  the  function  of  the  sexual  glands  is  not  usually  fol- 
lowed by  distinct  retrogression.  First  in  cases  in  which  the  sclerosing  process 
involves  numerous  ductless  glands  does  there  seem  to  be  in  women  a  distinct, 
and  in  men  a  marked  retrogression  of  the  hairiness  and  the  genital  organs. 

In  the  cases  of  multiple  ductless  glandular  sclerosis  in  which  there  have 
been  autopsies  there  is  always  to  be  found  a  marked  sclerosis  of  the  supra- 
renal cortex.  Further  there  should  be  observed  in  eunuchoidism  whether  in 
rare  cases  there  does  not  exist,  in  addition  to  the  hypoplasia  of  the  sexual 
glands,  a  hypoplasia  of  the  suprarenal  cortex. 

Finally  Variot  and  Pironneau  have  described  a  case  which  was  character- 
ized by  marked  disturbance  in  growth,  absence  of  any  hairiness  at  all  (eye- 
brows, lashes,  and  almost  complete  baldness  of  the  head) .  They  have  desig- 
nated this  case  "nanisme  type  senile"  and  refer  to  two  entirely  analogous 
observations  by  Gilford  Hastings  and  Sir  [Jonathan]  Hutchinson.  In  the 
last  case  the  suprarenals  were  found  to  be  sclerosed.  Variot  therefore  con- 
cludes that  these  vegetative  disturbances  depend  on  a  loss  of  the  function 
of  the  suprarenal  cortex.  It  seems  to  me,  however,  that  in  the  case  of  Hutch- 
inson there  was  an  insufficient  examination  of  the  other  ductless  glands.  Also 
Gilford  Hastings  points  this  out,  and  I  hold  that  it  is  not  impossible  that 
this  case  constitutes  multiple  ductless  glandular  sclerosis  in  childhood,  al- 
though I  am  not  in  a  position  to  prove  this.  Perhaps  some  objections  may 
be  made  against  this  view.  At  least  I  shall  speak  again  of  these  cases  under 
the  consideration  of  multiple  ductless  glandular  sclerosis. 

It  is  also  doubtful  whether  the  dwarf  described  by  v.  Recklinghausen 
should  be  grouped  under  cortical  insufficiency.  In  a  dwarf  eighteen  years 
old  who  had  died  in  convulsions,  v.  Recklinghausen  found  an  apparently 
chronic  tuberculous  caseation  of  both  suprarenals.  The  individual  was  95 
cm.  tall  and  weighed  io3>^  kilograms.     The  measurements  correspond  to  about 


352  THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

those  of  a  three-  or  four-year-old  child.  The  body  dimensions  were  well 
proportioned.  The  epiphysial  junctures  were  retained,  the  penis  and  the 
testicles  were  rather  small.  If  we  were  already  disposed  to  regard  a  loss 
of  the  suprarenal  function  as  the  cause  of  the  disturbance  in  growth,  we 
would  have  to  hold  responsible  the  suprarenal  cortex,  as  hypoplasia  of  the 
chromaffin  tissue  rather  produces  a  tall,  weak,  individual.  I  regard  as  more 
likely  that  here  we  are  dealing  with  a  true  dwarfism  and  that  the  supra- 
renal caseation  constitutes  an  accidental  complication. 

On  reviewing  the  preceding  material,  we  find  that  it  is  a  question  if 
the  observations  are  to  be  referred  to  an  isolated  withdrawal  of  the  cortical 
function.  The  observations  seem  rather  to  suggest  that  from  the  cortex 
there  proceeds  a  furthering  influence  on  the  genital  sphere  and  especially  on 
the  hairiness,  an  assumption,  as  we  shall  see  later  receives  essential  support 
through  corresponding  manifestations  in  hyperplastic  conditions  of  the  cortex. 
These  observations  furnish  no  support  for  the  assumption  that  loss  of  the 
function  of  the  suprarenal  cortex  leads  to  manifestations  of  intoxication. 

b.  Conditions  of  H)T)erf unction  of  the  Suprarenal  Apparatus 

Here  we  are  interested  especially  in  tumors  of  the  suprarenal  appara- 
tus, which  usually,  but  not  always,  are  associated  with  conditions  of  hyper- 
function. 

I.  Tumors  that  Proceed  from  the  Chromaffin  Tissue 

These  seem  to  be  very  rare.  Kilster  describes  two  cases  of  glioma  of  the 
suprarenals,  one  aft'ecting  a  fourteen-month  child  whose  entire  right  supra- 
renal had  been  converted  into  a  tumor,  while  in  the  left  suprarenal  was 
found  a  tumor  occupying  the  site  of  the  medulla.  Numerous  metastases  were 
present. 

In  the  second  case  the  findings  were  accidental.  Kilster  regarded  these 
tumors  as  a  glioma,  Wiesel  as  a  growth  made  up  of  formative  cells  of  the 
sympathetic,  although  Schilder  has  lately  described  a  certain  glioma  of  the 
sympathetic  and  regards  Kmler^s  case  as  glioma.  More  recently  there  have 
been  described  chromafiin  tumors,  in  part  too  proceeding  from  the  paragan- 
glia, by  Weichselbaum,  Manasse,  Stangl,  Monckeherg,  and  Kolisko.  Kolisko's 
case  (reported  by  v.  Neusser  and  Wiesel)  was  that  of  a  vigorous,  otherwise 
healthy,  man  who  suddenly  died  during  cocaine  anesthetization  on  account 
of  the  extraction  of  a  tooth.  Here  was  found  a  bilateral  suprarenal  tumor 
made  up  of  chromaffin  tissue,  and  very  rich  in  adrenalin.  v.  Neusser  and 
Wiesel  regard  this  case  as  adrenalin  intoxication.  Very  interesting  is  the 
case  of  Wiesel,  a  tumor  of  the  sympathetic  in  a  two-year-old  child  with  arterio- 
sclerosis which  resembled  histologically  the  sclerosis  produced  experimentally 
in  animals  by  adrenalin.     Hence  it  seems  that  these  tumors  can  be  associated 


CONDITIONS  OF  HYPERFUNCTION  OF  THE  SUPRARENAL  APPARATUS   353 

with  hyperfunction  of  the  chromaffin  tissue.  For  this  also  speaks  the 
associated  cardiac  hypertrophy  that  is  so  frequently  found. 

Moreover,  there  should  be  mentioned  here  the  case  of  Kawashima.  In 
this  case  were  found  multiple  skin  fibromata  proceeding  from  the  con- 
nective-tissue sheath  of  the  nerves,  and  also  tumors  of  the  suprarenal  medulla. 
Kawashima  discusses  the  association  of  neurofibromata  with  diseases  of  the 
nervous  system.  He  points  out  that  neurofibromata  are  very  frequently 
associated  with  general  symptoms  (disturbances  of  nutrition,  intellectual  dis- 
turbances, gastrointestinal  affections,  certain  visual  disturbances,  headaches, 
spasms,  depressed  states,  and  alterations  in  the  sexual  sphere)  and  believes 
that  these  as  well  as  the  general  symptoms  are  the  expression  of  an  affection  of 
the  nervous  system.  There  should  also  be  mentioned  two  cases  of  paragangli- 
oma reported  by  M.  Herde.  Both  cases  were  those  of  chromaffin  tumors. 
In  one  case  there  existed  arteriosclerosis,  in  the  other  genuine  "Schrumpf- 
niere."  Finally  I  mention  a  case  of  Sazuki's  (chromaffin  tumor  of  the 
suprarenal  medulla)  and  of  E.  Hedinger's  (struma  medullaris  cystica  supra- 
renalis) . 

The  question  as  to  whether  there  exist  conditions  of  hyperfunction  of  the 
chromaffin  otherwise  than  when  due  to  tumor  has  been  recently  discussed. 
It  is  noteworthy  that  numerous  authors  take  the  negative  attitude  concerning 
this  question,  at  least  as  far  as  chromaffin  tissue  is  concerned.  In  tumors  of 
the  chromaffin  tissue  we  have  learned  to  recognize  a  group  of  clinical  condi- 
tions, which  we  may  regard  as  due,  with  great  probability,  to  an  increased 
function  of  the  chromaffin  tissue. 

i\re  we  then  justified  in  regarding  similar  clinical  conditions  as  the  ex- 
pression of  a  h5^erfunction  of  the  chromaffin  tissue,  even  where  a  patho- 
logico-anatomical  substratum  has  not  as  yet  been  found  for  them? 

Originally  French  authors  (Pilliet,  V agues.  Aubertin  and  Amhard)  en- 
deavored to  explain  the  increase  of  blood-pressure  in  interstitial  nephritis 
by  an  increase  in  the  function  of  the  suprarenal  cortex,  as  they  often  met  with 
strikingly  large  suprarenals  in  cases  with  hypertonia.  Josue  has  assumed  such 
in  the  atheromatosis  associated  with  hypertonia.  After,  however,  we  had 
recognized  the  significance  of  the  chromaffin  tissue  for  the  regulation  of  blood- 
pressure,  Beaujard  regarded  it  as  regulative  against  increased  circulation  of 
toxic  products  in  the  organism,  which  would  be  conditioned  on  the  lessened 
eliminatory  capabilities  of  the  kidney.  Apparently  the  chromaffin  tissue 
alone  seems  to  be  significant  for  the  pathogenesis  of  this  condition,  in  so  far 
as  we  might  wish  to  bring  it  into  correlation  with  the  suprarenal  apparatus. 
•The  question  should,  however,  be  formulated  as  to  whether  secondary  hyper- 
functional  conditions  of  the  chromaffin  tissue  occur  as  the  reaction  to  other 
processes  in  the  body,  processes  that  are  released  eventually  by  a  permanent 
reflex  condition  of  over-excitement  of  the  centers  of  this  system  lying  in  the 
medulla  oblongata  or  in  the  brain  stem;  also  we  should  consider  the  possibility 
23 


354  THE  DISEASES  OF  THE  SUPRARENAL  APPARATUS 

as  we  have  discussed  in  Basedow's  disease,  that  these  centers  are  primarily 
in  a  state  of  hyperirritability  on  grounds  that  are  not  at  all  clear.  If  this 
were  so,  we  could  speak  of  a  true  neurosis. 

Wiesel  was  the  first  who  referred  the  disease  process  associated  with 
hypertonia  to  a  condition  of  hyperfunction  of  the  chromaffin  system.  He 
found  hyperplasia  of  the  chromaffin  tissue  in  twenty-two  chronic  and  some 
acute  cases  of  nephritis,  and  in  a  case  of  aortic  insulhciency — all  cases 
showed  cardiac  hypertrophy — the  hyperplasia  affecting  the  suprarenal  me- 
dulla as  well  as  the  paragangha.  Later  Schur  and  Wiesel  tried  to  demonstrate 
in  such  cases  the  increased  amount  of  adrenalin  in  the  blood,  by  means  of  the 
Ehrmann-Meltzer  reaction.  The  hyperplasia  of  the  chromaffin  tissue  was  cor- 
roborated by  numerous  authors,  of  whom  are  named  Schmorl,  Goldzieher,  and 
Molnar  and  Comisatti.  Both  Schmorl  and  Goldzieher  also  found  an  increase  in 
the  adrenalin  content  of  the  suprarenals.  Other  authors,  as  Bittorj\  found  no 
such  hyperplasia.  Certain  negative  cases  do  not  seem  to  me  to  mean  very 
much,  as  not  every  case  of  hyperplasia  need  be  distinct.  The  statements  as 
to  the  increased  adrenalin  content  of  the  serum  have  met  with  more  contra- 
diction. It  is  certain — with  the  following  my  own  experiences  agree — that 
in  numerous  cases  with  hypertonia  the  frog's-eye  method  fails.  But  also 
other  line  biological  methods  give  negative  results,  for  Sclilaycn,  using  Meier's 
vessel-strip  method,  and  A.Frdnkel,  using  the  myographic  method,  found  the 
serum  of  nephritics  even  less  active  than  normal  serum.  These  behaviors 
were  complicated  by  the  foreign  serum,  as  Schlayer  ascertained,  in  a  manner 
that  could  not  be  overlooked.  The  myographic  method  is,  however,  from  its 
very  nature  hard  to  interpret,  ior  Fleming  and/,  also  on  the  use  of  an  adrenalin 
Ringer-solution,  saw  inhibition  of  the  movements  and  the  tonus  of  a  rabbit's 
uterus.  O'Connor,  using  the  Laeicin-Trendclenburg  frog  muscle  method  came 
to  like  results.  He  found  that  the  activity  of  the  serum  was  conditioned  not 
only  by  its  adrenalin  content  but  also  by  other  substances,  that  first  get  into 
the  serum  on  coagulation.  We  therefore  can  say  only  that  up  to  the  present 
the  biological  methods  do  not  furnish  a  certain  evidence  for  the  increased 
adrenalin  content  of  the  serum.  On  the  strength  of  this,  however,  I  do  not 
feel  justified  in  denying  the  teaching  of  Schnr  and  Wiesel.  In  favor  of  it 
speaks  in  addition  to  the  hyperplasia  of  the  chromaffin  tissue  the  increased 
diuresis,  which  agrees  with  the  increased  amount  of  sugar  in  the  blood  as 
shown  by  E.  Neubancr  and  also,  as  I  beheve,  with  alterations  in  the  distri- 
bution of  the  blood  as  seen  in  experimental  hyperadrenalinemia.  Very 
frequently  we  see  congestive  conditions  in  the  lungs,  in  the  brain  (retinal 
hemorrhages,  apoplexies),  and  in  the  liver.  In  beginning  decompensation 
very  often  the  swelling  of  the  liver  is  the  first  to  appear.  Again,  in  such 
conditions,  very  often  at  the  beginning,  we  see  a  slight  grade  of  hyper- 
globuha;  later  the  count  of  red  blood  cells  is  very  often  reduced  (destructive 
effect  of  chronic  adrenalinizing  on  the  erythropoiesis).     Finally  we  tind  the 


CONDITIONS  OF  HYPERFUNCTION  OF  THE  SUPRARENAL  APPARATUS   355 

count  of  neutrophilic  cells  mostly  at  the  upper  limits  of  the  normal  or  even 
slightly  exceeding  these. 

As  to  the  question  why  interstitial  nephritis  is  associated  with  an  increase 
of  function  of  the  chromaffin  tissue  I  shall  not  enter  into  here  more  inti- 
mately. In  many  cases,  for  instance,  in  the  nephritis  of  scarlet  fever,  the 
disease  of  the  kidney  is  primary,  in  other  cases  the  contracted  kidney  can  only 
be  a  partial  manifestation  of  the  general  arteriosclerosis  of  the  small  blood- 
vessels. Such  a  general  arteriosclerosis  must  lead  refiexly  to  a  hypertonia 
through  lowering  of  the  resistance,  if  the  accessory  amount  of  blood  should 
be  driven  through  the  capillary  system  of  the  muscles,  etc.  Finally  it  is 
conceivable  that  the  increase  of  function  of  chromaffin  tissue  (as  for  instance 
in  tumors  of  the  sympathetic,  perhaps  also  in  premature  arteriosclerosis  of 
diabetics,  or  in  transition  of  diabetes  into  contracted  kidney)  is  the  primary 
factor  {Frank's  hypertonic  diathesis). 

Still  less  clear  is  the  significance  of  the  chromaffin  tissue  for  the  coming 
into  existence  of  the  atheromatosis.  As  is  known,  chronic  adrenalizing  of 
rabbits  can  produce  sclerosis  of  the  great  vessels  (Josue,  Erb,  and  others). 
This  is  an  affection  of  the  media.  The  vascular  lesions  in  tumors  of  the  sym- 
pathetic are  also  affections  of  the  media.  Braun,  however,  by  the  intraven- 
ous injection  of  minimal  doses  of  adrenalin  could  produce  atheromatosis  of 
the  small  vessels.  The  ordinary  arteriosclerosis  of  the  large  vessels,  that 
occurs  without  increase  of  blood-pressure,  has  nothing  at  all  to  do  with 
the  chromaffin  tissue;  it  depends  on  a  primary  degeneration  of  the  elastic 
elements. 

Finally,  some  observations  as  to  the  influence  of  hyperfunction  of  the  chrom- 
affin tissue  on  the  carbohydrate  metabolism.  In  hypertonics  we  find,  as  already 
mentioned,  hyperglycemia.  The  kidneys  adapt  themselves  to  a  very  gradual 
increasing  amount  of  sugar  in  the  blood,  without  glycosuria  {v.  Noorden). 
In  many  cases  of  diabetes  mellitus,  and  especially  in  advanced  cases,  much 
speaks  for  the  view  that  here  also  there  is  a  slight  overproduction  of  adrenalin 
{Falta,  Newburgh,  and  Nobel).  That  the  administration  of  this  escapes 
detection  by  the  known  biological  methods  is  not  to  be  wondered  at,  when  on 
the  one  hand  we  take  into  consideration  the  unreliability  of  the  biological 
methods  (see  above)  and  on  the  other,  consider  what  monstrous  dilution, 
I  gm.  of  adrenalin,  which  under  circumstances  may  produce  much  sugar  in  the 
urine,  must  experience  when  injected  subcutaneously  in  man.  Such  a  slight 
increase  in  adrenalin  production  may  very  well  be  overshadowed  by  the 
counter-regulations  without  leading  to  increase  in  blood-pressure.  On  the 
contrary  the  toxic  components  seem  to  dissociate,  as  is  shown  by  the  prema- 
ture arteriosclerosis  so  frequently  observed  in  diabetes.  An  exact  histological 
study  of  the  same  has  not  as  yet  been  made.  Finally  we  should  point  out  the 
frequent  transition  of  diabetes  into  contracted  kidney.  On  the  grounds  de- 
tailed the  negative  standpoint  that  G.  Bayer,  and  Broking  and  Trendelenburg 


356  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

have  taken  against  the  assumption  of  a  functional  increase  of  the  chromaffin 
tissue  in  certain  forms  of  diabetes  melUtus,  does  not  seem  to  me  a  priori  to 
be  justified. 

2.  Tumors  that  Proceed  from  the  Cortex 

These  appear  to  possess  greater  cHnical  interest  than  the  tumors  of  the 
chromaffin  tissue.  The  knowledge  that  they  may  be  associated  with  hyper- 
function  of  the  cortical  system  is  one  of  the  achievements  of  recent  years.  In 
a  clinical  respect  we  can  distinguish  two  groups  of  cortical  tumors.  In  one 
of  the  groups  belong  chiefly  the  sarcomata,  lymphosarcomata,  carcinomata, 
alveolar  sarcomata,  endotheliomata,  the  melanotic  carcinomata,  and  the  cysts 
(literature  in  Bullock  and  Sequeira ,  Frew,  Glynn,  Tilestone,  Winkler,  Hanschen, 
and  Arnaud).  These  seem  to  bring  forth  only  the  usual  symptoms  of  a 
benign  or  mahgnant  tumor.  We  shall  not  discuss  this  group  any  further. 
The  other  group  embraces  the  numerous  cases  of  adenomata  of  the  cortical 
substance. 

These  show  great  diversity  in  their  point  of  departure.  They  may  pro- 
ceed from  the  cortex  itself,  or  may  originate  in  the  separated  germs  of  the 
cortical  system  in  the  kidney,  or  in  the  genitaha,  etc.  The  process  concerned 
in  such  adenomata  may  be  that  of  a  simple  hyperplasia,  that  may  either  run 
its  course  without  symptoms  or  give  rise  simply  to  the  local  manifestations  of 
tumor,  or  may  assume  malignant  character,  and  then  show  great  inclination 
for  the  formation  of  metastases.  Finally  these  tumors  may,  without  the  men- 
tioned tumor  symptoms,  lead  to  profound  alterations  of  the  organism,  that 
with  a  certain  probability  may  be  regarded  as  the  expression  of  a  hyperfunc- 
tion  of  the  cortex.  Before  I  enter  into  the  consideration  of  the  clinical  mani- 
festations, I  should  like  to  refer  to  the  demonstration  of  Bourneville  that  in 
idiots  with  ''sclerose  tubereause  du  cerveau"  there  are  regularly  found  in  the 
cortex  of  the  suprarenals  lumps  that  Pellizzi  regards  as  adenomata  of  the 
suprarenals. 

The  hypernephromata  consist  in  round,  oval,  or  polygonal  cells,  of  an  epi- 
thelial character.  The  cells  are  often  of  many  shapes.  As  the  suprarenals 
are  of  mesodermal  origin,  it  is  readily  intelligible  that  the  cells  often  assume  a 
mesodermal  character,  and  in  their  histological  structure  approach  primitive 
sarcomata  (Glynn).  They  are  different,  however,  from  the  suprarenal  sar- 
comata proper;  true  lumina  are  never  observed  in  them  (Woolley). 

The  simplest  form  clinically  is  represented  by  so-called  Grawitz  tumors. 
These  may  originate  in  the  kidneys  (Grawitz)  or  the  ovaries  (Vonwiller)  or  in 
the  tail  of  the  pancreas  (R.  Mohr).  Lately  their  origin  from  separated  germs 
of  the  suprarenals  has  been  combated  by  Stoerck  and  Zehbe,  while  R.  Mohr 
has  again  arrayed  himself  for  this  genesis.  In  the  clinical  respect  it  is  signifi- 
cant that  they  are  never  associated  with  alterations  in  the  genital  sphere. 
This  without  doubt  speaks  for  the  view  of  Stoerck  and  Zchhe.     At  most  we 


COXDITIOXS  OF  HYPERFrXCTIOX  OF  THE  SUPRAREXAL  APPARATUS   357 

must  assume  that  the  Granitz's  tumors  are  strumas  of  the  suprarenals  that 
analogously  to  strumas  of  the  thyroid  do  not  tend  to  be  associated  \Yith 
manifestations  of  h\-perf unction. 

When  the  Grawitzs  tumors  are  of  large  growth  they  may  lead  to  local 
oppressions  (pains  in  the  lumbar  region,  intercostal  or  femoral  neuralgias, 
and  when  there  is  pressure  on  the  kidneys  to  hematuria,  albuminuria,  cysturia, 
etc.),  or  they  degenerate  malignantly  and  lead  to  metastases  and  cachexia. 
Westphal  has  gathered  twenty-four  cases  from  the  literature,  and  has  added 
seven  cases  from  his  own  statistics. 

In  Graiiitz's  tumor  there  is  frequently  a  tendency  to  formation  of  cysts 
due  to  softening,  with  characteristic  chocolate-colored  content,  which  is 
eventually  demonstrable  on  puncture. 

It  is  true  that  Westphal  adduces  symptoms  that  indicate  a  hyperfunction 
of  the  chromaffin  tissue.  In  two  of  seven  cases  he  found  temporary  glyco- 
suria, in  three  cases  a  relative  increase  in  the  neutrophilic  cells  and  a  distinct 
increase  in  blood-pressure  in  the  early  stages.  I  beheve  that  these  symptoms 
are  only  of  a  secondary  nature,  called  forth  by  an  initial  irritation  of  the 
medullary  substances  by  the  gro-^dng  tumor.  It  is  worth  mentioning  that 
Bittorf  in  two  cases  of  unilateral  h}-pernephroma  also  found  symptoms  of  an 
Addison's  disease,  emaciation,  lassitude,  pigmentations,  and  low  blood-pres- 
sure. These  cases  also  showed  a  lymphocytosis.  It  seems  to  me  that  this 
furnishes  a  corroboration  of  my  view  that  the  manifestations  on  the  part 
of  the  chromaffin  tissue  (irritation  or  deticiency)  are  only  of  a  secondary 
nature.  Bittorf  also  observed  slight  psychical  symptoms  in  his  case  and 
believes  that  they  are  of  diagnostic  importance  and  they  do  not  occur  in 
tumors  of  the  kidneys  (v.  StriimpeU).  Both  Bittorf  s  cases  were  cured  on 
operation,  only  the  pigmentations  remaining  unaltered. 

Perhaps  the  following  two  cases  also  belong  to  this  group.  :■.  Xeusser 
mentioned  a  twenty-five-year-old  man  with  very  tense  pulse,  multiple  hemor- 
rhages in  the  brain.  The  section  showed  a  carcinoma  of  one  suprarenal. 
Vascular  system  and  kidneys  were  normal. 

In  addition:'.  Xeusser  cites  a  case  of  Frdnkel's.  an  eighteen-year-old  girl 
with  headaches,  vomiting,  and  high  pulse  tension.  Section  showed  a  vas- 
cular neoplasm  of  the  left  suprarenal:  the  kidneys  were  normal.  Here,  too, 
can  the  hj-perfunction  of  the  chromaffin  tissue  be  regarded  as  an  irritative 
symptom.  Conversely  in  rapidly  growing  cortical  tumors  symptoms  of  de- 
iiciency  of  the  chromaffin  tissue  may  occur. 

Of  very  great  interest  for  the  knowledge  of  the  internal  secretions  are 
those  adenomata  of  the  suprarenal  cortex  that  are  associated  with  hj-per- 
function  of  the  cortex.  In  the  clinical  picture  of  these  cases  there  seems  to  be 
an  appreciable  difference  according  to  whether  they  develop  in  the  entirely 
childish,  or  in  the  juvenile,  or  in  the  adult  organism. 

I.  With  the  development  of  such  hyperfunctionating  cortical  tumors  in 


358  THE   DISEASES    OF    THE    SUPRARENAL    APPARATUS 

the  cliildish  organism  there  occurs  an  enormously  accelerated  development  of 
the  body,  a  premature  development  of  the  genitalia.  Such  cases  are  described 
by  Cooke,  a  seven-year-old  female;  Tilesius,  a  four-year-old  female;  Ogle,  a 
three-year-old  female;  Calcott-Fox,  a  five-year-old  female;  Orth,  two  and 
one-half-year-old  female;  Dohhertin,  four-month-old  iem.a\e;Ritsche,  four-year- 
old  female;  Bullock  and  Sequcira,  eleven-year-old  female;  Linscr,  five-and- 
one-half-year-old  male;  Adams,  fourteen-and-three-fourth-year-old  male. 
In  the  case  of  Adams,  puberty  set  in  at  the  age  of  ten  years.  The  boy  was 
large  and  strong  muscularly.  Autopsy  showed  tumor  of  the  left  suprarenal 
proceeding  from  the  cortex.  A  careful  compilation  of  the  literature  has  been 
made  by  Xeiiratli-,  and  more  recently  by  Glynn.  Further  cases  are  reported 
by  Guthrie  and  W.  d^Este  Emery  (four-and-one-half-year-old  boy,  fat,  large 
tumor  of  the  suprarenal  cortex),  by  Richards  (seven-year-old  girl),  hy  Glynn 
and  by  French  (reported  by  Glynn) ;  and  perhaps  also  the  case  of  Guinon 
Bijou  belongs  here  (no  autopsjO- 

Some  cases  I  shall  quote  more  exactly.  The  case  of  Linser  was  that  of  a 
five-and-one-half-year-old  boy,  who  looked  like  a  youth  and  therefore  was 
admitted  into  the  men's  department  of  the  hospital.  He  was  138  cm.  tall, 
the  penis  was  8-9  cm.  long,  the  testicles  as  large  as  pigeon's  eggs,  the  pros- 
tate like  that  of  a  tifteen-year-old  boy,  the  musculature  was  well-developed. 
The  size  of  the  body,  the  ossification,  the  almost  complete  set  of  permanent 
teeth,  corresponded  fully  to  those  of  a  fifteen-year-old  boy.  The  upper 
length  was  larger  than  lower  length,  hence  childish  dimensions  were  present 
in  a  potentized  form.     The  hypophysis  was  normal  and  there  was  adiposity. 

The  case  of  Bullock  and  Sequeira  was  of  an  eleven-year-old  female  who 
looked  like  a  forty-year-old  woman.  Menstruation  had  set  in  at  the  age  of 
nine  and  three-fourth  years  and  from  this  time  on  there  developed  an  in- 
creasing adiposity.  The  girl  was  4  ft.  6  in.  high  and  weighed  6  stones.  3  lb. 
[87  lb.].  The  breasts  were  fully  developed.  Long  hairs  were  present  on  the 
genitaUa.  Autopsy  showed  a  large  tumor  of  the  left  suprarenal  consisting 
in  cells  of  zona  fasciculata,  with  numerous  metastases,  hyperplasia  of  the 
thyroid  and  the  parathyroids,  fully  developed  uterus  and  large  ovaries  with 
corpora  lutea  of  recent  date. 

The  case  of  Richards  was  that  of  a  seven-year-old  girl.  At  the  age  of 
five  she  developed  pubic  hair  and  hair  on  the  face.  At  seven  years  old  she 
looked  like  a  woman  twenty  years  old,  the  hairs  on  the  genitalia  were  fully 
developed,  and  hairs  were  present  on  the  side  of  the  face  and  on  the  site  of 
the  mustache. 

The  case  of  Glynn  was  that  of  a  girl  five  years  old.  In  the  third  year  of 
life  she  began  with  pains  in  the  abdomen  and  the  head,  later  apathy.  She 
was  as  large  as  a  girl  fourteen  years  old,  and  fat.  Hairs  were  present  on 
the  upper  lip,  on  the  pubis  and  on  the  back.  The  sexual  organs  were  espe- 
cially well  developed.     There  was  found  a  large  tumor  of  the  suprarenal 


CONDITIONS  OF  HYPERFUNCTION  OF  THE  SUPRARENAL  APPARATUS   359 

cortex,  ovaries  and  hypophysis  were  normal.  In  the  case  of  French  (seven- 
year-old  girl)  the  abnormal  hairiness  began  to  develop  as  early  as  the 
eighteenth,  month;  the  genital  organs  were  very  large;  here  also  was  found 
a  suprarenal  tumor. 

It  will  be  seen  that  the  condition  nearly  always  affects  girls.  Of 
seventeen  cases  offered  by  Glynn,  fourteen  were  of  the  female  sex.  What 
is  common  to  all  in  the  clinical  picture  of  these  cases  is,  as  Neurath  empha- 
sizes, the  premature  excessive  development  of  the  secondary  sexual  characters 
and  of  the  external  genitalia.  Neurath  mentions  that  in  this  category  of  pre- 
mature sexual  development,  the  function  of  the  generative  portion  is  on  the 
contrary  not  prematurely  developed.  This  does  not  always  point  to  an  espe- 
cially intimate  relation  between  the  suprarenal  cortex  and  the  interstitial 
glands.  Moreover,  common  to  almost  all  cases  is  adiposity,  furthermore  the 
accelerated  growth,  probably  with  retention  of  the  infantile  dimensions, 
and  the  accelerated  ossification  and  dentition.  The  development  of  the 
psyche  in  such  children  as  a  rule  does  not  keep  pace  with  the  bodily  develop- 
ment.    Also  the  development  of  the  sexual  instinct  is  usually  slow. 

II.  The  manifestations  that  occur  on  the  development  of  hypernephro- 
mata  in  the  juvenile  or  mature  organism  are  likewise  characterized  by  an  enor- 
mous influencing  of  the  sexual  sphere.  Here  also  I  would  enter  more  fully  in 
the  case  reports.  The  case  of  Bortz  and  Thumim  was  that  of  a  sixteen-and- 
three-fourth-year-old  girl.  At  first  she  had  developed  quite  normally,  then 
the  menses  ceased,  and  there  developed  a  luxuriant  deep  black  beard  and 
a  sparse  mustache.  Hairs  developed  on  the  chest  and  on  the  linea  alba,  the 
voice  became  deeper  and  universal  obesity  developed.  Death  occurred  as 
the  result  of  an  intercurrent  illness.  Section  revealed  atrophy  of  the  ovaries, 
■enormous  enlargement  of  the  thyroid  gland,  normal  hypophysis;  on  both 
sides  there  existed  a  suprarenal  tumor  rich  in  blood-vessels  that  had  ap- 
parently developed  only  from  the  cortex. 

Case  of  Winkler. — Sixteen-year-old  girl.  Abundant  black  hair  on  the 
upper  lip.     Uterus  small.     Tumor' of  the  right  suprarenal  with  metastases. 

Case  of  Bovin. — Twenty-eight-year-old  woman.  Two  labors,  then  cessa- 
tion of  menses  at  the  age  of  twenty-one.  Development  of  the  beard.  There 
is  also  an  abundant  growth  of  hair  on  the  abdomen.  Simultaneously,  the  de- 
velopment of  an  abdominal  tumor.  Operation  showed  a  large  ovarian  tumor 
proceeding  from  separated  suprarenal  germs.  The  patient  recovered  from 
the  operation,  the  uterus  became  larger  again,  menstruation  reappeared,  and 
the  abnormal  hairiness  disappeared.  However,  the  observation  after  opera- 
tion was  for  a  short  period  of  time  only. 

The  case  of  Hegar  perhaps  belongs  to  this  group  (abnormal  hairiness, 
uterus  duplex,  cystic  tumor  of  the  ovary).  Moreover,  perhaps  also  the  case 
of  Alberti.  In  this  case  menstruation  was  normal  up  to  the  nineteenth  year. 
Development  otherwise  normal.    Then  set  in  hypertrichosis,  development  of  a 


360  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

beard,  mustache,  and  hair  on  the  trunk.  At  the  same  time  a  tumor  developed 
in  the  abdomen.  Death  occurred.  Autopsy  showed  a  cystoma  pseudomu- 
cinosum  proceeding  from  the  right  ovary.  The  chtoris  was  appreciably 
enlarged  (autopsy  only  partial,  no  statement  as  to  the  suprarenals) . 

Case  of  Goldschwend. — Thirty-nine-year-old  woman,  had  five  children. 
Cessation  of  menses  three  years  ago.  For  four  months  pains  in  abdomen, 
development  of  an  abdominal  tumor,  development  of  a  mustache  and 
beard,  and  hair  on  the  abdomen,  malignant  adenoma  of  the  left  supra- 
renal, uterus  and  ovaries  small,  epiphysis  and  hypophysis  normal. 

Case  of  Launois,  Pinard,  and  Gallais. — Nineteen-year-old  girl.  Men- 
struated first  at  the  age  of  thirteen  years.  At  seventeen  violent  vomiting, 
gradually  colossal  obesity,  mental  changes.  Cessation  of  menstruation, 
emaciation,  then  diffuse  depilation,  and  only  then  hypertrichosis  and 
myasthenia.  The  girl  appeared  to  be  much  older  than  she  was,  black  beard 
and  mustache.     Tumor  of  the  right  suprarenal. 

Possibly  also  the  following  case  of  DalcJie  belongs  here;  twenty-eight-year- 
old  woman,  body  quite  feminine,  for  five  years  development  of  a  mustache 
and  beard  and  (after  miscarriage)  cessation  of  menstruation.  Breasts  well 
developed,  voice  feminine,  uterus  small,  atrophy  of  the  inner  genitalia,  hyper- 
trichosis on  abdomen,  slight  manifestations  of  hyperthyrosis,  there  were  no 
other  symptoms  of  a  suprarenal  tumor. 

Also  a  case  has  been  reported  that  began  at  the  menopause. 

Case  of  Sajiti. — Fifty-three-year-old  woman,  two  normal  pregnancies, 
menstruation  always  regular  until  six  years  ago.  Then  the  periods  became 
more  frequent,  until  the  woman  lost  blood  almost  constantly.  Enlargement 
of  the  abdomen,  enormous  obesity.  Autopsy  showed  a  tumor  of  the  kidney 
proceeding  from  separated  suprarenal  germs,  and  a  similar  tumor  of  the 
ovary.     No  statement  as  to  hairiness. 

Under  this  category  may  well  belong  the  case  of  Vollbracht.  mentioned 
by  V.  Neusscr  and  Wiescl.  The  case  was  designated  by  the  last  named 
authors  as  Addison's  disease  with  contrasexual  sexual  characters. 

Let  us  look  over  the  cases  I  have  mentioned.  In  women  simultaneously 
with  the  development  of  a  hypernephroma  there  occur  cessation  of  the 
menses,  hypertrichosis  of  a  definite  localization  (linea  alba,  growth  of  beard) 
and  obesity.  The  development  of  hypernephroma  at  the  menopause  ap- 
parently gives  rise  only  to  obesity. 

III.  Cases    of    Pseudohcrmaphrodilism. — Marchand    first    reported    the 
autopsy   findings  in   a   fifty-year-old   individual   who   in   life   was   always 
regarded  as  a  man. 

The  individual  showed  masculine  body  conformation  and  masculine  hairi- 
ness of  the  face;  autopsy  showed  a  hermaphroditismus  spurius  femininus.a 
very  large  penis-like  clitoris,  a  distinct  scrotum  and  a  rather  large  prostate; 
there  was  also  a  vagina  with  the  traces  of  a  hymen,  a  uterus,  and  atrophic 


CONDITIONS  OF  HYPERFUNCTION  OF  THE  SUPRARENAL  APPARATUS   36 1 

ovaries.  Finally  colossal  hypertrophy  of  the  suprarenal  cortex  and  a  large 
accessory  suprarenal.  A  similar  case  had  previously  been  reported  by 
Crecchio.. 

Three  cases  of  pseudohermaphroditismus  f emininus  by  Fiehiger:  Habitus 
and  hairiness  quite  masculine,  larynx  masculine,  penis  and  prostate  present, 
no  vasa  deferentia,  vagina,  uterus,  and  ovaries.  The  last  showed  the 
follicle  formation.  No  menstruation;  capable  of  cohabitation.  Masculine 
sexual  sense.  Very  large  suprarenals,  apparently  hyperplasia  of  the  cortex. 
Fiehiger  regards  these  cases  as  an  especial  teratological  type. 

Case  of  Engelhardt. — Fifty-nine  years.  Married  a  woman  at  the  age  of 
twenty-seven  years.  Erections  were  present,  but  only  weak  and  very  rare. 
Questionable  whether  ejaculations  were  present.  Beard  and  mustache. 
Facial  features  masculine.  Breasts  feminine,  hands  and  feet  slender.  Penis 
embedded  in  a  cushion  of  fat.  Hypospadia,  corpora  cavernosa  present. 
Scrotum  only  indicated  by  tissue  rich  in  fat,  testicles,  buttocks,  hips  and 
thighs  are  feminine.  Prostate  feebly  developed.  Autopsy  showed  an 
aberrant  suprarenal  struma  at  the  lower  pole  of  the  right  kidney.  The 
ovaries  were  small  and  dense,  with  sparse,  poorly  developed,  follicles. 

Here  also  belongs  the  case  of  Hepner  and  Ogston  and  furthermore  the  very 
interesting  case  of  Meixner  (case  III).  This  was  the  case  of  a  new-born 
child  with  pseudohermaphroditismus  masculinus,  bilateral  cryptorchidism, 
with  separated  and  enlarged  suprarenal  glandular  tissue  in  the  neighborhood 
of  the  testicles. 

V.  Neugebauer  mentions  in  his  large  work  thirteen  cases  of  pseudo- 
hermaphroditism with  suprarenal  tumors. 

Summarizing  the  cases  cited:  only  one  case  was  that  of  pseudohermaph- 
roditismus masculinus.  The  other  cases  were  pseudohermaphroditismus 
femininus.     All  cases  showed  a  bilateral  swelling  of  the  suprarenal  cortex. 

IV.  Finally  it  should  be  remembered  that  also  in  acromegaly  there  occur 
certain  cases  in  which  hyperplasia  of  the  suprarenals  is  observed  (Delille, 
Fischer,  and  Fischer  and  Schultze).  Fischer  and  Schultze  find  the  entire 
suprarenals,  cortex  as  well  as  medulla  hyperplastic,  while  Delille  observed 
only  a  hyperplasia  of  the  cortex.  It  is  very  probable  that  in  the  future  when 
we  pay  more  exact  attention  to  these  relations  we  will  find  hyperplasia  of 
the  suprarenals,  and  especially  of  the  cortex,  in  many  cases  of  acromegaly.  I 
would  also  call  attention  to  the  fact  that  in  many  cases  of  acromegaly,  there 
occurs  both  in  men  and  women  abnormally  abundant  hairiness.  In  women 
the  hairiness  may  assume  quite  the  masculine  type. 

Surveying  the  entire  field  of  facts,  one  is  surprised  by  the  wealth  of 
clinical  observations  that  properly  classified  demonstrate  that  from  the  su- 
prarenal cortex  there  proceeds  an  enormous  influence  on  the  growth  of  the 
body,  and  the  genital  sphere,  and  on  the  hairiness,  therefore  on  an  important 
secondary  sexual  character.     Until  a  short  time  ago  these  connections  were 


362  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

scarcely  suspected.  In  the  books  of  Neiisser  and  Wiesel  on  the  diseases  of  the 
suprarenal  glands  they  are  hardly  taken  up.  As  to  what  concerns  the  al- 
terations in  the  organisms  that  occur  in  hyperplasia  of  the  suprarenals,  that 
is  in  conditions  of  hyperfunction,  it  is  worthy  of  note  that  they  are  different 
according  to  the  age  at  which  such  hyperplasia  develops.  Their  action  occurs 
earliest  in  pseudohermaphroditism.  Here  their  development  occurs  in  fetal 
life.  That  the  development  of  such  cortical  hyperplasias  stands  in  a  causal 
relationship  with  the  development  of  pseudohermaphroditism  is  hardly  at 
all  probable;  when  one  considers  that  up  to  the  present  insufficient  attention 
has  been  paid  to  such  relationship,  it  would  not  do  to  assume  that  the  hyper- 
plasias occur  constantly  in  pseudohermaphroditism.  It  is  much  more  likely 
that  they  are  only  a  partial  manifestation  of  the  malformation,  which  would 
lend  to  them  at  all  events  a  definite  expression.  It  has  already  been  men- 
tioned, they  occur  almost  exclusively  in  pseudohermaphroditismus  femininus. 

In  the  age  of  childhood  we  see  with  development  of  the  tumors  of  the 
suprarenal  cortex  a  premature  development  of  the  entire  organism,  a  sort 
of  transient  gigantism  associated  with  potentized  childish  dimensions  and 
premature  development  of  the  genital  organs,  a  clinical  picture  that  in 
almost  all  respects  is  similar  to  that  observed  in  the  development  of  tumors 
of  the  pineal  gland  in  childhood.  Whether  hyperplasia  of  the  suprarenal 
cortex  is  frequently  present  with  tumors  of  the  pineal  in  childhood  is  as  yet 
not  certain.  Up  to  the  present  it  has  been  observed  in  one  case  only.  As  we 
shall  see  later  in  the  development  of  tumors  of  the  sexual  glands  in  childhood 
there  occur  the  same  chnical  pictures,  even,  if  possible,  better  pronounced. 
Here  also  future  studies  must  decide  as  to  the  behavior  of  the  suprarenal 
cortex.  Apparently  there  exists  an  intimate  connection  between  these  three 
forms  of  premature  development  and  it  would  not  be  unlikely  that  the  bond 
of  union  is  the  suprarenal  cortex.  At  any  rate,  a  certain  influence  of  the  supra- 
renal cortex  on  the  growth  is  evident;  with  this  agrees  also  the  occurrence  of 
cortical  hyperplasia  in  acromegaly.  Just  as  evident  is  a  certain  stimulating 
influence  on  the  development  of  the  sexual  glands.  Apparently  there  exists 
here  a  reciprocal  correlation,  as  hyperplastic  changes  in  the  suprarenal  cortex 
occur  during  rut  in  animals  and  in  pregnancy  {Guiyesse,  Stoerck  and  v.  Haberer) . 
In  this  also  can  be  seen  a  certain  relation  of  the  suprarenal  cortex  to  growth. 
As  is  known,  women  who  are  pregnant  and  whose  epiphysial  junctures  are  still 
open  often  take  on  a  renewed  growth  during  the  pregnancy.  And  finally  there 
can  be  seen  on  it  a  relation  to  the  growth  of  the  fetus,  if  it  be  not  forgotten  that 
the  hyperplastic  alterations  in  the  anterior  lobe  of  the  hypophysis  may  also 
produce  and  maintain  the  tendency  to  increased  growth. 

When  the  cortical  tumors  develop  in  the  fully  developed  organs  the  mani- 
festations are  quite  different.  Thus  far  the  cases  have  been  favorable. 
Here  there  comes  about  a  pronounced  disturbance  of  the  functions  of  the 
sexual  glands  with  involution  of  the  uterus  and  in  addition  a  tendency  to 


ADDENDUM  363 

obesity  and  to  the  development  of  hairiness,  both  of  which  with  respect  to 
abundance  and  locaHzation  are  entirely  masculine.  The  influence  of  the 
suprarenal  cortex  on  the  hairiness  is  especially  unmistakable  in  all  the  con- 
ditions mentioned.  We  find  abnormal  hairiness  in  pseudohermaphroditismus 
femininus,  in  the  premature  development  in  childhood,  in  the  cortical  tumors 
that  develop  in  the  adult  organism,  perhaps  just  in  the  cases  of  acromegaly 
with  hyperplasia  of  the  cortex,  and  finally,  as  is  known,  in  pregnancy,  in 
which  hair  begins  to  grow  in  places  that  otherwise  represent  the  virile  type. 
Therefore  it  seems  necessary  that  in  future,  when  the  question  is  asked  as  to 
which  influences  the  secondary  sexual  characters  have  to  thank  for  their 
origin,  attention  should  also  be  paid  to  the  suprarenal  cortex.  The  near  re- 
lationship that  the  suprarenal  cortex  and  the  substances  of  the  sexual  glands 
show  embryologically  and  morphologically  seems  also  to  exist  in  the  function 
of  these  parts. 

Treatment. — Up  to  the  present,  only  the  operative  treatment  of  hyper- 
nephromata  has  been  tried.  In  every  case  an  early  diagnosis  is  important,  as 
the  tumors  are  often  malignant.  That  result  may  be  expected  from  operation 
is  shown  by  the  previously  mentioned  case  of  Bovin.  Perhaps  in  certain 
cases  a  result  may  be  expected  from  the  use  of  the  X-rays. 

3.  Tumors  of  the  Suprarenals   that  Apparently    Consist  in  Cortex  and 

Medulla 

Davidsohn  has  reported  a  case  of  melanoma  of  the  suprarenals  with  nu- 
merous melanotic  metastases.  Histologically  he  found  cells  of  the  zona 
fasciculata  and  glomerulosa,  and  also  cells  of  the  medulla.  The  metastases, 
on  chemical  examination  and  on  blood-pressure  tests,  were  found  to  contain 
adrenalin.  Moreover,  perhaps  here  belongs  the  case  of  Neuberg,  in  which  in- 
deed no  adrenalin  could  be  demonstrated,  but  in  which  an  enzyme  was  found 
which  could  change  adrenalin  into  a  black  pigment.  Neuberg  believed  that 
the  adrenalin  further  produced  in  the  metastases  was  the  mother  substance  of 
the  melanin  found  there.  These  cases  were  not  accompanied  with  disturb- 
ances of  the  sexual  sphere. 

Addendum 

Glynn,  from  a  review  of  the  literature,  arrives  at  about  the  same  opinions 
as  the  author  with  reference  to  the  relation  of  the  suprarenal  cortex  to  the 
other  ductless  glands  and  to  sex.  He  adduces  as  a  further  argument  for  the 
view  that  renal  hypernephromata  arise  from  suprarenal  rests  the  fact  that 
such  rests  are  rare  in  the  kidney,  while  hypernephromata  are  common  kidney 
tumors;  and  that  suprarenal  rests  in  other  localities,  though  comparatively 
common,  especially  in  early  life,  rarely  produce  tumors  at  all. 


364  THE    DISEASES    OF    THE    SUPRARENAL    APPARATUS 

Caniioji,  Shohl,  and  Wright  subjected  cats  to  fright,  and  uniformly  ob- 
tained glycosuria.     This  glycosuria  was  not  present  after  adrenalectomy. 

Glynn  {E.  E.).     The  adrenal  cortex,  its  rests  and  tumors;  its  relation  to  other  ductless 
glands  and  especially  to  sex.     The  Quarterly  Journal  of  Medicine,  Vol.  V,  1911-1912, 

P-  157- 

Cannon  {W.),  Shohl  (.1.   T.),  and  Wright  (W .  S.).     Emotional  glycosuria.     Am.  J. 

Physiol.,  1911-1912,  pp.  280-287. 


CHAPTER  IX 

STATUS   LYMPHATICUS   AND    STATUS   HYPOPLASTICUS 

A.  Status  Lymphaticus 

Here  at  the  conclusion  of  the  discussion  of  the  suprarenal  apparatus  we 
might  add  some  remarks  on  the  so-called  status  lymphaticus,  because  recent 
investigations  have  shown  that  it  possesses  a  close  relation  to  conditions  of 
hypofunction  of  the  chromaffin  tissue.  As  I  have  already  mentioned  in  the 
chapter  on  the  thymus  gland,  the  tendency  among  many  authors  is  for  the 
separation  of  status  thymicus  from  status  lymphaticus.  The  frequent  co- 
incidence of  a  large  thymus  gland  and  status  lymphaticus  can  perhaps  be 
explained  by  the  increase  in  the  lymphoid  elements  in  the  thymus  gland. 
The  great  interest  that  clinicians  and  pathological  anatomists  have  turned  on 
status  lymphaticus  depends  on  the  fact  that  it  is  associated  with  cases  of 
sudden,  quite  inexplicable,  death.  It  is  the  great  service  of  A.  Paltauf  to 
have  recognized  that  here  there  is  an  underlying  profound  constitutional 
alteration,  which  is  always  associated  with  lymphatism. 

How,  now,  is  status  lymphaticus  characterized?  Here  it  seems  that  I 
must  give  vent  to  a  conception  that  has  forced  itself  upon  me  especially  in  the 
study  of  the  diseases  of  the  ductless  glands.  I  am  forced  to  distinguish  a 
primary  and  a  secondary  lymphatism.  The  first  develops  in  earliest  youth, 
and  has  on  this  account  a  profound  influence  on  the  development  of  the  whole 
organism.  It  is  characterized  by  the  following  earmarks  (in  this  I  follow  the 
description  of  A.  Paltauf  and  especially  the  new  excellent  description  by 
Kolisko).  Under  normal  circumstances  we  find  that  in  childhood  the  lym- 
phatic apparatus  is  essentially  more  strongly  developed  than  in  adults. 
Hence  it  comes  about  that  the  leucocytic  formula  of  the  child  shows  a  greater 
content  of  lymphocytes.  The  years  of  childhood  are  those  in  which  lymphat- 
ism is  especially  prone  to  develop.  The  involution  of  the  lymphatic  appara- 
tus follows,  chiefly  at  puberty.  In  true  status  lymphaticus  the  involution  of 
an  already  abnormally  developed  lymphatic  apparatus  remains  absent. 
We  find  enlarged  follicles  at  the  base  of  the  tongue,  hyperplasia  of  the  entire 
pharyngeal  lymphatic  ring,  lymphoid  growth  in  the  nose,  enlargement  of  the 
lymphatic  glands  in  the  neck,  in  the  axillary  and  inguinal  regions,'hyperplasia 
of  Peyer^s  patches,  red  bone  marrow,  large  spleen,  and  more  or  less  large 
thymus  gland.  Very  frequently  we  found  hypoplasia  and  narrowness  of  the 
aorta  and  the  whole  arterial  vascular  tract.  The  heart  likewise  is  often  ab- 
normally small,  although  it  can  also  be  hypertrophic.     Commonly  there  is 

365 


366  STATUS    LYMPHATICUS    AND    STATUS    HYPOPLASTICUS 

dilatation  of  the  left  ventricle  with  diffuse  clouding  of  the  endocardium,  and 
not  rarely  remaining  behind  in  the  development  of  the  genitals,  slight  de- 
velopment of  the  secondary  sexual  characters,  retarded  onset  of  menstruation^ 
and  retarded,  lessened,  sexual  instinct. 

According  to  the  new  researches  of  Wiesel  and  Hedinger  there  is  regularly 
associated  with  these  characteristics  an  abnormally  slight  development  of  the 
chromaffin  tissue.  The  medullary  substance  of  the  suprarenals  is  essentially 
lessened,  and  the  paraganglia  are  illy  developed.  According  to  v.  Siiry  this 
underdevelopment  of  the  chromaffin  tissue  mostly  sets  in  after  birth. 

In  status  lymphaticus  there  occurs  in  the  blood  picture  a  relative  or  ab- 
solute reduction  of  the  neutrophilic  leucocytes  and  a  corresponding  increase 
in  the  mononuclear  cells,  eventually  also  a  hypereosinophilia  {v.  Neusser). 
This  fact  is  readily  intelligible  when  the  experiments  of  Bertelli,  SchweegeYy 
and  myself  are  considered.  On  the  one  hand  it  is  possible  that  the  giving  off 
of  mononuclear  cells  of  the  blood  is  increased  in  hyperplasia  of  the  lymphatic 
apparatus,  and  on  the  other  hand  we  must  assume  that  an  enormous  trophic 
influence  is  exerted  on  the  production  of  the  neutrophilic  elements  of  the  bone 
marrow,  this  influence  proceeding  from  the  chromaffin  tissue  by  mediation  of 
the  sympathetic;  here  the  production  of  neutrophilic  elements  by  the  bone 
marrow  is  probably  diminished. 

It  is  very  possible  that  this  anomaly  of  constitution  is  the  cause  of  the 
sudden  death.  If  the  chromaffin  tissue  is  underdeveloped  and  not  attained 
to  a  great  functional  breadth,  it  may,  if  especial  demands  are  made  on  it 
especially  by  a  cold  bath  or  by  the  effects  of  narcosis  of  the  sympathetic 
nervous  system,  suddenly  give  out.  This  form  of  status  lymphaticus  may  well 
be  designated  an  "entite  morbide."  The  opinion  has  been  expressed  that 
substances  are  given  off  from  the  lymph-glandular  system  to  the  blood  path, 
substances  that  in  their  action  are  in  a  certain  way  antagonists  of  adrenalin 
{v.  Neusser).  Also  in  this  sense  can  we  consider  this  form  of  status  lymphati- 
cus under  the  diseases  of  internal  secretion.  Such  individuals,  as  Eppinger  and 
Hess  point  out,  not  rarely  show  symptoms  of  the  relatively  increased  vagal 
tonus  (inclination  to  sweats,  certain  anomalies  of  the  pulse  and  respiration, 
etc.).  The  slight  functional  breadth  of  the  chromaffin  tissue  is,  however, 
especially  important  for  the  fate  of  such  individuals.  Often  the  blood-pres- 
sure lies  near  the  lower  limits  of  normal,  as  Mi'inzcr  emphasizes,  the  pulse 
shows  a  slight  force  [Wurfkraft].  Accorchng  to  Wiesel  such  individuals  are 
especially  precUsposed  to  Addison's  disease,  in  that  tuberculous  and  other 
processes  become  established  in  the  hypoplastic  suprarenal  medulla,  and  by 
spreading  to  the  cortex  call  forth  the  typical  picture  of  Addison's  disease. 

The  secondary  form  of  status  lymphaticus  is  characterized  by  the  fact 
that  the  signs  of  lymphatism  predominate  only  later,  the  development  origi- 
nally being  normal.  According  to  the  age  of  the  individual,  according  to 
whether  the  lymphatism  is  only  transitory  or  remains  permanent,  does  the 


STATUS    HYPOPLASTICrS  367 

development  become  more  or  less  inhibited.  In  childhood,  as  already  H. 
Kundrat  mentioned,  rachitis  leads  to  lymphatism  not  infrequently,  as  do  also 
tetany,  the  exudative  diathesis,  especially  scrofulosis,  and  a  series  of  other 
infectious  processes.  In  adolescent  and  adult  individuals  occasion  is  given 
for  a  temporary  or  a  permanent  lymphatism  by  the  vagal  neurosis,  bronchial 
asthma,  chronic  infectious  diseases,  especially  lues  and  tuberculosis,  osteo- 
malacia, and  especially  the  affections  of  the  ductless  glands.  In  a  great  num- 
ber of  cases  perhaps  there  occurs  at  first,  through  chemotactic  influences,  only 
a  slight  mononucleosis  of  the  blood,  and  only  later  a  slight  h^-perplasia  of  the 
lymphatic  apparatus,  therefore  a  forme  fruste;  in  other  cases,  especially  in 
many  formations  of  ductless  glandular  afi'ections.  the  hyperplasia  of  the  lym- 
phatic apparatus  may  be  fully  developed.  Of  the  ductless  glandular  diseases 
should  be  mentioned  especially  Addison's  disease,  myxedema,  Basedow's  dis- 
ease, acromegaly,  tetany,  and  dystrophia  adiposo-genitalis.  Also  in  some 
cases  that  we  must  regard  as  true  eunuchoids  we  found  appreciable  mononu- 
cleosis of  the  blood.  It  is  self-evident  that  mononucleosis  is  a  symptom  with 
many  meanings,  and  in  itself  speaks  nothing  for  the  diagnosis  of  status  lym- 
phaticus.  Thus  we  found  it  strikingly  present  also  in  many  severe  forms  of 
diabetes  mellitus  in  which  autopsy  showed  no  status  lymphaticus.  It  is  very 
probable  that  under  secondary  lymphatism  are  concealed  numerous  and  di- 
verse conditions,  in  part  chronic  inflammatory  in  nature,  the  dift'erentiation 
of  which  perhaps  can  first  be  made  by  a  careful  microscopical  examination  of 
the  lymphatic  apparatus. 

The  great  difiiculty  in  the  diagnosis  of  status  lymphaticus  in  vivo  is  made 
prominent  in  the  comprehensive  exposition  of  this  subject  brought  out  a  short 
time  ago  by  v.  Xeiisser.  ?.  Xeusser  relates  how  important  it  is  to  have  in 
mind,  in  consideration  of  the  minute  factors,  the  possibihties  of  an  existing 
status  lymphaticus,  because  the  infectious  diseases  and  especially  the  most 
diverse  noxious  agents  frequently  take  on  a  characteristic  expression  on 
the  ground  of  this  constitutional  anomaly  and  often  pursue  their  course 
unfavorably. 

B.  Status  H5^oplasticus 

In  several  works.  Bartel  has  indicated  a  form  of  developmental  disturbances 
that  he  designates  hypoplastic  constitution.  It  is  frequently,  but  not  always, 
associated  with  status  lymphaticus.  The  body  size  of  such  indiA'iduals  is  on 
the  average  normal.  Often  the  fatty  tissue  is  very  well  developed.  There  is 
found  hA-poplasia  and  narrowness  of  the  vascular  system  and  poverty  of  the 
smooth  musculature  of  the  aorta  (Wiesner).  and  in  addition  faulty  develop- 
ment of  the  sexual  glands  and  secondary  sexual  characters.  The  sexual 
glands  are  indeed  of  normal  size,  the  ovaries  often  even  enlarged;  microscop- 
ically there  is  found,  however,  prohferation  of  the  connective  tissue  {Herrmann 
and  Kyrle) .     When  status  lymphaticus  is  present  an  atrophic  stage  can  follow 


368  '      STATUS    LYMPH ATICUS    AND    STATUS    HYPOPLASTICUS 

the  stage  of  hyperplasia.  Bartel  assumes  as  the  cause  of  this  condition  con- 
genital predisposition  on  the  one  hand,  and  on  the  other  hand  damaging  of 
the  sensitive  childish  organism,  especially  by  infectious  diseases.  The 
length  of  life  of  such  individuals  is  mostly  shortened,  and  56  per  cent,  of  the 
cases  investigated  by  Bartel  died  between  the  fourteenth  and  twenty-fifth 
years  of  life.  The  status  hypoplasticus  is  thus  not  entirely  identical  with 
status  lymphaticus,  but  also  not  with  true  infantilism,  which  will  be  described 
in  another  chapter. 


CHAPTER  X 
THE  DISEASES  OF  THE  SEXUAL  GLANDS 

The  knowledge  of  the  internal  secretion  took  its  origin  from  the  sexual 
glands.  Broivn-Sequard  injected  himself  with  testicular  extract  and  be- 
lieved that  thereby  he  could  obtain  a  sort  of  rejuvenation  of  the  organism. 
The  experiments  on  the  sexual  glands  also  first  brought  the  knowledge  that 
the  function  of  the  ductless  glands  is  in  a  high  degree  independent  of  the  nerv- 
ous system.  Goltz  transected  the  spinal  cords  of  animals  and  observed  that 
these  animals  conceived,  carried  their  young  normally,  gave  birth,  and  suckled, 
in  spite  of  the  fact  that  the  ovaries  were  cut  off  from  the  higher  nervous 
centers.  The  later  researches  on  transplantation  of  the  sexual  glands  showed 
this  independence  in  still  higher  degree.  Ribbert,  and  later  Knaner,  trans- 
planted the  ovaries  under  the  skin  in  animals  and  observed  that  in  such 
animals  there  occurred  no  involution  of  the  uterus  such  as  would  otherwise 
tend  to  occur  after  castration.  Halban  showed  that  also  in  the  youthful 
incomplete  organism  transplanted  ovaries  could  exercise  their  protective 
influence  on  the  development  of  the  genital  apparatus.  The  ovaries  were 
transplanted  under  the  skin  of  new-born  guinea-pigs.  After  one  year 
Graffian  follicles  and  ova  were  present  in  the  transplants.  Uterus  and 
breasts  developed  normally,  while  in  the  castrated  control  animals  breasts 
and  genitalia  remained  quite  rudimentary.  Foges  and  later  Steinach  then 
showed  that  after  transplantation  of  the  testicles  the  secondary  sexual  char- 
acters develop  (although  not  always  completely),  while  in  the  castrated 
control  animals  the  development  of  these  characters  suffer  marked  damage. 

While  not  until  lately  has  experimental  pathology  furnished  an  insight 
into  the  function  of  the  sexual  glands,  clinical  observation  from  the  very  be- 
ginning has  stirred  the  interest  of  physicians  and  the  laity,  because  the  in- 
stinct of  procreation  affects  everything  that  lives.  The  influence  that  the 
loss  of  the  sexual  glands  exercises  on  the  configuration  of  the  body  and  the 
development  of  the  secondary  sexual  characters  has  been  known  since  antiq- 
uity. Just  those  malformations  that  stand  in  especial  relations  with  the 
sexual  glands,  such  as  hermaphroditism,  or  the  development  of  the  so-called 
contrasexual  character,  belong  to  these  curiosities  that  since  that  time  have 
been  exhibited  in  show-booths  [museums].  Also  the  problem  of  heredity  is 
intimately  associated  with  the  function  of  the  sexual  glands. 

Finally  this  problem  has  always  had  a  great  significance  for  breeders 
of  animals. 

24  369 


37°  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

Embryological,  Anatomical,  and  Physiological  Preliminary  Remarks. — 

For  the  comprehension  of  the  physiology  and  pathology  of  the  sexual  glands 
it  is  necessary  to  distinguish  sharply  between  these  proper  and  the  accessory 
genital  apparatus.  The  rudiments  of  the  accessory  apparatus  (primordial 
kidneys  with  Wolffian  and  Mullerian  ducts)  are  common  to  both  sexes. 
According  as  to  whether  sexual  glands  develop  into  testicles  or  ovaries  do 
the  indiflerent  rudiments  develop  into  epididymis,  paradidymis,  vasa 
deferentia,  and  prostate,  or  into  epoophoron,  paroophoron,  Gartner's  ducts, 
tubes,  uterus,  and  vagina. 

Two  parts  of  the  sexual  glands  are  to  be  distinguished:  the  interstitial 
glands^  (consisting  in  the  so-caWedLcydig's  interstitial  tissue),  and  the  specific 
glands  of  generation  (in  man,  seminiferous  tubules,  Sertoli's  cells  [?]  in 
women,  the  follicular  apparatus). 

A.  The  Interstitial  Glands 

The  Leydigs  interstitial  cells  are  epithelioid  cell  accumulations  imbedded 
in  the  sexual  glands  of  the  male.  They  are  filled  with  acidophilic  and  baso- 
philic granules,  show  great  similarity  to  the  cells  of  the  suprarenal  cortex, 
and  like  these  are  of  mesodermal  origin  {Simon,  1892,  Wallart,  Seitz).  These 
cell  formations  develop  enormously  at  the  time  of  puberty.  In  women  we 
understand  by  "interstitial  glands"  a  cell  complex  that  develops  from  the 
atretic  follicles  of  the  theca  interna.  In  women  these  cells  develop  very 
markedly  at  the  time  of  puberty,  and  temporarily  during  pregnancy  {Wallart.) 
I  must  not  omit  to  state  that  the  view  is  held  by  many  that  in  the  highest 
female  mammals,  in  the  human  species  and  in  monkeys,  the  interstitial  glands 
are  inconstant  {Bucura).  This  has  been  denied  on  other  sides,  and  I  would 
only  state  here  that  the  function  of  the  interstitial  glands  in  man  is  to-day 
already  so  sharply  dehmited  and  that  it  is  concerned  with  functions  so  im- 
portant, functions  that  influence  the  conformation  of  the  body  in  such  an 
extensive  manner,  that  it  is  hard  to  believe  that  so  important  an  organ  is 
absent  in  women. 

According  to  the  view  of  some  of  the  authors  the  interstitial  glands  govern 
in  man  in  this  special  field  the  development  of  the  primary  and  secondary 
sexual  characters,  and  are  hence  of  great  importance  for  the  formation  of 
the  body. 

The  distinction  between  interstitial  glands  and  generative  apparatus  is 

'  The  distinction  between  "internal  secretory  and  germinative"  that  up  to  the  present  has 
been  the  practice  in  the  literature,  and  that  was  also  retained  by  me  in  my  article  on  the  diseases 
of  ductless  glands  in  Mehr-Siaehelin's  handbook,  must  be  rejected  by  me,  as  it  seems  to  me  to 
lead  to  the  coarsest  misunderstandings.  Steinach  designates  the  "innersekretorische"  glands 
as  "Pubertatsdriise."  It  seems  to  be  undoubted  however  that  the  "internal  secretory"  activity 
of  the  generative  apparatus  is  very  considerable.  Indeed  the  entire  teaching  of  hormones  has 
been  developed  from  the  influencing  of  the  growth  of  mammary  glands  through  the  hormone  of 
the  fetus  or  of  the  chorionic  epithelium,  that  is  properly  speaking,  the  ovum. 


THE    INTERSTITIAL    GLANDS  37 1 

based  on  a  series  of  clinical  observations  and  experimental  facts.     The  clinical 
observations,  which  I  shall  describe  first,  are  concerned  with  cryptorchidism. 

Variot  first  pointed  out  the  great  difference  between  kryptorchides  ab- 
dominaux  and  kryptorchides  inguinalis.  The  first  is  associated  with  obesity 
and  broadening  of  the  pelvis;  the  larynx  remains  small,  the  voice  remains 
high  and  shrill,  the  beard  and  the  pubic  hairs  do  not  grow;  microscopical 
examination  shows  marked  connective  tissue  proliferation  in  the  extremely 
small  testicles.  I  shall  speak  of  this  form  later  in  the  consideration  of 
eunuchoidism. 

In  the  adult  kryptorchides  inguinales,  in  which  the  testicles  remain  behind 
in  the  inguinal  canal,  the  sexual  potency  may  be  present.  Such  individuals 
may  have  ejaculations  without  the  expulsion  of  spermatozoa.  They  are 
therefore  potent,  but  sterile.  These  individuals  have  an  entirely  masculine 
habitus,  the  voice  changes,  there  occur  growth  of  beard  and  normal  hairiness 
of  the  trunk,  the  musculature  is  vigorous,  the  dimensions  of  the  skeletons  are 
normal,  etc.  Here  the  function  of  the  interstitial  glands  is  retained,  while 
that  of  the  generative  glands  is  not  developed.  In  twenty  cases  of  cryptor- 
chic  testicles,  Tandler  did  not  find  spermatogenesis  in  a  single  case,  but  did  find 
normal  interstitial  substance.  Therefore,  in  cryptorchidism  the  disturb- 
ance in  the  development  of  the  glands  of  generation  is  the  rule,  while  the 
disturbance  of  that  of  the  interstitial  glands  is  found  only  in  severe  cases. 

The  first  experimental  observations  were  made  by  Ancel  and  Bouin. 
They  ligated  the  vasa  deferentia  and  found  that  after  a  time  spermatogenesis 
had  entirely  disappeared,  while  interstitial  glands  were  retained.  These 
animals  showed  complete  normal  development  of  the  masculine  habitus. 
Tandler  and  Grosz  further  showed  that  after  intensive  Rontgen  irradiation 
of  the  testicles  of  young  Cerviden  the  spermatogones,  on  account  of  their 
greater  sensitiveness  become  destroyed,  while  the  interstitial  glands  were 
retained.  In  these  animals  the  masculine  sexual  characters  developed  in 
entirely  normal  manner.  Latterly  Simmonds  has  shown  that  after  Rontgen 
irradiation  there  are  always  found  individual  undamaged  seminal  tubules, 
that  can  again  regenerate;  but  the  significance  of  this  finding  must  not  be 
estimated  too  high.  Lately  Steinach  has  reported  concerning  transplanta- 
tion experiments  that  place  the  matter  in  a  secure  position.  Ifjin  young 
sucklings  the  testicles  are  transplanted,  the  secondary  sexual  characters 
proceed  to  develop  entirely  normally.  The  histological  examination  shows 
that  the  spermatozoa  are  entirely  absent.  Clinical  observation  was  thus 
entirely  corroborated  by  experiment. 

As  in  such  animals  also  the  external  genitalia  develop  entirely  normally, 
it  is  to  be  assumed  that  the  interstitial  glands  exercise  an  important  influence: 
I.  On  the  development  of  the  generative  glands.     An  isolated  develop- 
ment of  these  without  the  interstitial  glands  is  not  known  in  the  male 
sex. 


372  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

2.  On  the  accessory  genital  apparatus. 

3.  On  the  so-called  secondary  sexual  characters. 

Hence  the  question  is  explained  in  the  male  sex.  As  has  been  mentioned 
it  is  hard  to  assume  that  in  women  such  an  important  organ  should  be 
absent. 

Although  it  is  now  established  that  the  interstitial  glands  exercise  an 
entirely  essential  influence  on  the  development  of  the  secondary  sexual 
characters,  we  must  still  regard  the  question  of  the  genesis  of  the  secondary 
sexual  characters  and  their  relations  to  the  sexual  glands  as  one  that  is 
much  argued.  There  is  no  uniformity  in  the  definition,  even  of  the  sec- 
ondary sexual  characters.  Dancin  understands  by  them  any  sexual  char- 
acters that  are  characteristic  for  the  sex  in  question,  but  which  have  nothing 
directly  to  do  with  reproduction. 

R.  Muller  divides  the  secondary  sexual  characters  into  physical  and 
mental,  and  further  divides  them  into: 

1.  Such  as  have  entered  into  an  intimate  relationship  with  the  propaga- 
tion and  nurture  of  the  young  animals:  for  example,  female  pelvis, 
mammary  glands,  temperament,  sexual  instinct,  maternal  love. 

2.  Such  in  which  are  shown  an  immediate  dependence  on  sexual  glands: 
skeleton,  muscular  system,  skin-appendages  (antlers,  horns,  combs, 
etc.),  formation  of  the  larynx,  swelling  of  the  thyroid  gland,  etc. 

3.  Such  that  are  only  mediately  dependent  on  the  sexual  glands:  internal 
organs,  different  psychical  activity,  etc. 

I  wish  from  the  beginning  to  limit  myself  to  these  two  definitions.  My 
attitude  toward  them  will  be  stated  later. 

First  I  shall  describe  more  in  detail  the  distinguishing  features  between 
the  [human]  male  and  female  bodies,  following  the  exposition  of  Novak. 
The  female  and  male  bodies  are  far  more  like  each  other  up  to  the  time  of 
puberty  than  later.  Before  puberty  both  show  the  infantile  type,  although 
extensive  dift'erenccs  exist  even  in  the  earliest  period  of  embryonal  life. 
For  instance  the  pelvis  may  be  recognized  as  feminine  as  early  as  the  fifth 
month  of  embryonal  existence  {Fehling).  At  the  time  of  puberty  the  growth 
in  both  sexes  is  essentially  increased.  In  the  male  the  larynx  now  enlarges, 
the  voice  changes,  the  growth  of  the  beard  begins  to  be  more  evident;  in  the 
female,  the  breasts  develop,  the  characteristic  form  of  pelvis  becomes  more 
prominent,  the  figure  becomes  rounded  and  an  abundant  deposit  of  fat  is 
found  especially  on  the  hips.  In  both  sexes  there  now  occurs  a  growth  of 
pubic  and  axillary  hairs,  the  former  in  women  remaining  bounded  above  by 
a  horizontal  line,  while  in  man  it  closes  above  in  the  form  of  a  triangle.  In 
man  the  body  size  is  on  the  average  greater,  the  horizontal  circumference  of 
the  head  is  slighter  in  relation  to  the  body  height,  in  woman  the  capacity  of 
the  head  is  less,  as  is  also  the  extension  of  the  facial  part.  In  man  the  ex- 
tremities are  longer  in  relation  to  the  length  of  torso,  in  woman  this  is  re- 


THE    INTERSTITIAL    GLANDS  373 

versed.  Ip.  women  the  shoulder-girdle  is  relatively  small,  the  hips  broader, 
hairs  of  the  head  in  woman  are  much  longer,  the  hairiness  of  the  body  is 
absent.  Michaeli's  quadrangle  is  broader  in  woman,  the  sacrum  is  less  curved 
and  is  shorter,  the  symphysis  is  broader  and  lower,  the  pubic  angle  is  greater, 
the  ihac  fossae  are  broader,  the  transverse  extension  of  the  pelvis  is  greater, 
the  pelvic  entrance  and  exit  are  greater  and  wider.  The  glandular  substance 
in  the  breast  is  always  developed  even  in  the  virgin,  the  nipples  are  more 
prominent,  and  more  easily  erectile.  In  addition  there  is  in  woman  a  less 
number  of  erythrocytes  per  cubic  millimeter  of  blood.  Then  there  are 
differences  in  the  psyche,  that  become  more  prominent  from  the  time  of 
puberty. 

I  would  now  briefly  sketch  those  problems  that  seem  to  me  most  im- 
portant for  the  evaluation  of  the  secondary  sexual  characters  and  for  their 
genesis. 

Almost  ah  of  the  distinguishing  signs  that  have  been  mentioned  may 
be  included  under  Darwin's  definition.  The  mammary  glands  seem  to  me 
to  form  an  exception.  Much  seems  to  speak  for  the  fact  that  the  female 
mammary  glands  are  a  primary  sexual  character,  or  rather  that  they  should 
be  directly  ascribed  to  the  generative  apparatus.  We  cannot  say  of  them 
that  they  have  nothing  to  do  directly  with  propagation,  for  in  mammals 
the  brood  would  be  annihilated  if  the  mammary  glands  were  to  cease  to 
functionate.  We  can,  however,  go  farther  and  suppose  that  the  growth  im- 
pulse and  mammary  glands  experience  in  women  emanates  not  from  the 
interstitial  glands,  but  from  the  generative  apparatus,  that  there  exists 
no  development  of  the  glandular  substances  (certainly  not  of  the  fat  sub- 
stances) without  development  of  the  follicular  apparatus,  and  that  the 
most  extensive  growth  impulse,  namely  that  during  pregnancy,  proceeds 
from  the  generative  apparatus,  equally  if  we  regard  as  the  source  of  the 
mammary  hormone  the  growing  fetus  or  the  chorionic  epithelium.  We 
shall  enter  more  fully  into  this  question  later. 

A  further  moot  point  is  whether  the  secondary  sexual  characters  are 
performed  from  the  ovum — as  to  the  question  whether  before  or  after  con- 
ception, I  shah  not  enter  into  here  at  all — or  whether  they  develop  in  the 
masculine  or  feminine  direction  under  the  influence  of  the  sexual  glands. 
Lenhossek  and  Halban  hold  the  opinion  that  the  total  sexual  characters  are 
somewhat  preexistent  and  that  the  sexual  glands  exercise  only  a  protective 
action  on  their  development.^  Another  view  that  stands  rather  bluntly 
opposed  to  that  just  described  is  that  the  sexual  glands  furnish  a  direct 
formative  stimulus  on  the  sexual  characters.     Recently  Steinach  on  the 

1  Also  Tandler  upholds  the  opinion  that  the  sexual  sphere  of  action  of  the  secondary  sexual 
characters  as  well  as  those  of  the  germinal  glands  are  preexistent.  Tandler  and  Grosz  mention 
in  this  connection  that  the  so-called  secondary  sexual  characters  are  only  characters  of  species 
and  enter  into  relation  to  the  genital  sphere  only  secondarily. 


374  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

ground  of  transplantation  experiments  inclines  to  this  view.  Finally  Biedl 
supposes  a  hermaphroditic  rudiment  of  the  sexual  glands.  The  secondary- 
sexual  characters  develop  either  in  a  masculine  or  a  feminine  direction 
according  as  to  whether  the  development  of  the  masculine  or  feminine 
internal  secretory  sexual  glands  predominate.  The  occurrence  of  heterolog- 
ous sexual  characters  is  explained  by  Biedl  by  the  supposition  that  the 
internal  secretory  portion  of  the  sexual  glands  that  belongs  to  the  other  sex 
obtains  the  upper  hand. 

A  further  problem  lies  in  the  fact  whether  the  sexual  characters  in  their 
development  especially  depend  exclusively  on  the  sexual  glands,  or  whether 
much  more  do  they  not  rather  receive  decisive  influences  from  the  other 
ductless  glands. 

The  discussion  of  all  these  questions  makes  necessary  not  only  the  resort 
to  experimental  pathology  and  physiology,  but  to  an  abundance  of  clinical 
observations.  It  seems  to  me  therefore  suitable  to  describe  first  the  genera- 
tive apparatus,  then  to  detail  the  most  important  clinical  observations  and 
only  later  to  enter  into  the  discussion  of  these  questions.  I  need  hardly 
emphasize  that  judging  from  the  contradictory  nature  of  the  opinions,  the 
discussion  must  be  strongly  tinged  subjectively. 

B.  The  Generative  Apparatus 

As  previously  mentioned,  the  interstitial  glands  are  of  mesodermal  origin. 
This  has  also  been  assumed  for  the  generative  apparatus,  although  to  me 
the  \-iew  seems  very  noteworthy  that  the  generative  apparatus  (spermato- 
gonia in  man.  foUicular  apparatus  in  women)  develop  out  of  the  primordial 
cells.  Then  the  interstitial  glands  and  generative  apparatus  are  differenti- 
ated embryologically.  Primordial  follicles  and  Sertoli's  cells  are  demon- 
strable already  at  an  early  embryological  stage. 

We  shall  first  take  note  of  the  development  of  the  generative  glands  and 
their  influence  on  the  total  organism,  in  woman.  The  development  of  the 
foUicular  apparatus  is  quite  gradual.  First  at  the  time  of  puberty,  together 
with  the  beginning  of  maturation  of  the  interstitial  glands  does  it  come  to 
full  development;  at  the  same  time  too  with  an  enormous  growth  impulse 
for  the  breasts  and  the  beginning  of  menstruation.  While  now  in  man  after 
complete  maturity  there  enters  the  condition  of  rather  continuous  function  of 
the  sexual  glands  and  especially  the  generative  apparatus,  in  woman  the 
activity  of  the  sexual  glands  and  especially  of  the  generative  apparatus 
is  subjected  to  periodic  variation.  With  the  periodically  recurring  ovula- 
tion and  menstruation,  there  enters  into  the  vital  processes  a  noticeable  wave 
movement  that  has  been  deeply  studied  by  Goodman,  Jacobi,  Rabutau, 
Reinl,  Ott,  and  others.  We  must  distinguish  a  premenstrual  period,  a  period 
of  menstruation  and  a  postmenstrual  interval.     During  the  premenstrual 


THE    GENERATIVE    APPARATUS  375 

period  there  are  found  signs  of  a  gradually  increasing  vitality  of  the  internal 
organism,  that  rapidly  reduces  during  the  bleeding.     In  the  seven  or  nine 
days  immediately  before  menstruation  the  blood-pressure  increases,  it  falls 
rapidly  with  the  beginning  of  the  flow,  and  reaches  its  lowest  value  at  the 
close  of  the  period.     With  this  variation  in  blood-pressure  are  associated 
variations  in  the  erythrocyte  count.     In  the  premenstrual  period  the  ery- 
throcyte count  may  lie   i   to  l^  milhons  higher  than  toward  the  end  of 
menstruation.     It  is  very   possible  indeed    that  just  as    in  tetany,    these 
variations  in  the  erythrocyte  count  are  to  a  great  degree  the  expression  of  an 
increased  or  diminished  tonus  of  the  vessels;  for  which  view  speaks  also  the 
careful  blood-pressure  measurements.     In  connection  with  it  may  stand 
too  the  strong  permeation  of  many  organs  with  blood.     Moreover  in  the 
premenstrual  period  there  is  found  a  higher  level  of  bodily  temperature  that 
becomes  prominent  especially  in  latent  diseases  (Reinl).     On  the  day  pre- 
ceding and  the  day  following  menstruation  the  temperature  is  the  lowest. 
In  many  individuals  there  may  also  be  demonstrable,  in  the  premenstrual 
period,  a  shght  neutrophilic  hyperleucocytosis  and  a  slight  heightening  of 
the  coagulability  of  the  blood.     Also  the  respiratory  volume  is  often  raised 
in  the  premenstrual  period,  while  it  is  shghtly  decreased  during  menstrua- 
tion (L.  Zuntz).     Many  of  the  manifestations  detailed  seem  to  me  to  point 
to  an  increased  function  of  the  chromaffin  tissue.     With  this  may  be  con- 
nected the  observation  that  in  the  premenstrual  period  the  glycosuric  ac- 
tion of  adrenahn  is  heightened.     Moreover  there  is  found  an  increase  in 
reflex  excitability  and  often  a.  higher  mental  alertness  and  capacity,  while 
during  menstruation  there  often  occurs  a  certain  mental  obtuseness.     Known 
for  a  very  long  time  is  the  swelling  of  the  thyroid  gland  in  the  premenstrual 
period    (struma   antemenstruahs,   Heidenhain).     It  is   further   stated  that 
before  rut  and  in  the  premenstrual  period  the  suprarenal  cortex  increases  in 
size.     Also  the  interstitial  glands  show  the  same  behavior  during  this  period, 
apparently  also  does  this  hold  true  for  the  glandular  hypophysis.     At  least 
such  a  conclusion  seems  suggested  by  the  similar  alterations  of  these  ductless 
glands  during  pregnancy;  perhaps  there  is  also  found  in  the  premenstrual 
period  an  increased  growth  of  any  beard  that  may  be  present  (Halban). 
Finally  it  is  known  that  the  mammary  glands  often  swell  slightly,  and  in 
rare  cases  even  in  the  virgin  may  secrete  a  slight  amount  of  colostrum. 
Further  the  nipples  often  show  an  increased  erectibiHty  and  are  painful. 

What  now  is  the  cause  of  this  rhythmically  occurring  menstrual  wave? 
Pfluger  developed  a  theory  that  monthly  ovulation  leads  by  reflex  paths  to  a 
hyperemia  of  the  pelvic  organs,  thereby  causing  menstruation.  Pflilger's 
law  has  been  made  untenable  by  the  knowledge  that  the  influence  of  the 
ovaries  in  the  organism  is  independent  of  the  nervous  system  and  depends 
on  the  giving  off  of  substances  to  the  blood-path.  Hence  it  must  be  modified 
to  state  that  the  influence  of  the  internal  secretion  of  the  generative  apparatus 


376  THE    DISEASES    OF    THE    SEXL^A.L    GLANDS 

on  the  organism  is,  through  the  maturation  of  the  ovum,  increased  in  a 
rhythmic  manner.  It  is  now  urged  against  the  dependence  of  menstruation 
on  ovulation  that  not  rarely  menstruation  and  ovulation  do  not  occur  at 
the  same  time,  but  that  under  circumstances  ovulation  can  take  place  after 
menstruation  (Leopold  and  Mironou\  Ravaiw).  Frdnkel  has  therefore  upheld 
the  view  that  the  retrogression  of  the  corpus  luteum  gives  rise  to  menstrua- 
tion. According  to  the  view  of  most  authors  there  can,  however,  be  attrib- 
uted to  corpus  luteum  at  most  a  postponing  but  not  a  releasing  [auslosende] 
action  (Halban).  Halban  would  principally  ascribe  to  the  oxoilation,  that 
is  to  the  sexual  glands,  only  a  protective  but  not  a  formative  influence  on 
menstruation  or  on  rut  and  on  the  cychcal  menstrual  phenomena,  pointing 
out  the  known  fact  that  after  even  a  long  time  after  bilateral  ovarectomy 
the  menstrual  wave  may  reappear.  Numerous  extensive  statistics  exist  as 
to  this  question;  I  mention  only  the  statement  of  Pfistcr  that  in  on  an  average 
of  12  per  cent,  of  castrated  women  menstruation  reappeared  and  that  among 
116  castrations  vicarious  menstruation  from  the  bowel  or  the  nose  occurred 
for  a  time  in  cases.  Finally  it  must  be  pointed  out  that  in  a  great  per- 
centage of  cases  after  castration  there  exist  cyclical  menstrual  molimina 
(backache,  nausea,  colics,  etc.).  Of  course  these  molimina  occur  when  the 
uterus  is  removed  and  the  ovaries  remain  behind  in  the  body.  Halban  is 
therefore  of  the  opinion  that  the  menstrual  wave  is  released  not  from  the 
ovary  itself,  but  by  an  as  yet  unknown  agent  and  that  much  the  more  the 
ovary  itself  reacts  to  this  agent  in  an  especially  sensitive  way,  and  this  reac- 
tion of  the  ovary  first  brings  the  menstrual  wave  to  its  complete  fulfillment. 
I  would  not  subscribe  unreservedly  to  the  view  of  Halban.  The  de- 
pendence of  menstruation  on  ovulation  is  in  any  case  very  considerable. 
Halban  himself  has  shown  that  in  baboons,  which  have  a  menstruation 
similar  to  that  of  human  beings,  menstruation  is  retained  after  transplanta- 
tion of  the  ovaries.  On  the  other  hand  after  ovarectomy,  rut  remains 
away  with  almost  every  case.  Lately  Adler  has  shown  that  subcutaneous 
injection  of  watery  extract  of  ovaries  calls  forth  in  virginal  animals  altera- 
tions in  the  internal  genitalia,  especially  the  uterus,  that  remind  one  of  the 
changes  that  take  place  during  rut.  In  two  amenorrheic  women  in  whom 
pieces  of  mucous  membrane  were  obtained  from  the  uterus  by  curcttement 
before  and  after  injection  of  this  extract,  microscopical  examinations  of  these 
pieces  showed  that  there  were  menstrual  alterations  of  the  mucous  mem- 
brane. As  after  castration  the  menstrual  wave  is  recovered  after  a  time  in 
an  attenuated  form,  this  does  not  seem  to  me  quite  inexplicable.  We  can 
imagine  that  the  menstrual  wave  that  has  existed  for  several  years  may  under 
circumstances  continue  for  a  while  after  castration,  if  the  sexual  life  has 
once  been  fully  developed.  The  difficult  point  according  to  my  view  would 
lie  in  the  question  whether,  in  youthful  persons  in  whom  menstruation  is 
mostly  absent,  the  development  of  the  wave  would  be  entirely  prevented 


THE    GENERATIVE    APPARATUS  377 

by  castration.  I  believe  that  this  would  be  the  case,  just  as  the  sexual  Kfe 
fails  to  develop  in  those  castrated  in  early  youth.  The  circumstance  that 
ovulation  and  menstruation  do  not  always  occur  at  the  same  time  does 
not  seem  to  me  very  essential.  It  is  conceivable  that  the  acme  of  the  in- 
ternal secretory  function  of  the  maturing  follicle  and  the  reaction  of  the 
organism  due  to  this  in  many  cases  occur  before  the  extrusion  of  the  egg,  in 
fashion  similar  to  that  which  Halhan  assumes  for  the  function  of  the  chori- 
onic epithelium  in  pregnancy.  While  therefore  ovulation  is  independent  of 
menstruation,  ovulation  may  continue  to  exist  when  menstruation  is  ab- 
sent. This  is  satisfactorily  demonstrated  by  the  fact  that  women  a  long 
time  amenorrheic  may  conceive.  Indeed  ovulation  may  take  place  in 
women  who  have  never  menstruated;  then  are  found  eventually  only 
cyclical  swelling  of  the  uterine  mucous  membranes,  or  cyclical  leucorrhea 
{Ogorek) . 

Pregnancy. — Even  after  fructification  the  ovulation  shows  certain  starts 
[Ansatze]  {Ravano-Fellner) ,  then  it  ceases  entirely,  and  menstruation  ceases 
with  it.  The  corpus  luteum  persists.  Probably  the  cessation  of  ovulation 
is  to  be  referred  to  persistence  of  the  corpus  luteum,  or  both  manifesta- 
tions are  to  be  referred  to  the  developing  fetus  or  much  more  to  the  develop- 
ment of  the  chorionic  epithelium.  I  cite  the  following  from  known  facts 
that  are  important  for  the  understanding  of  these  relationships.  In  the 
cow  there  not  rarely  occurs  persistence  and  hypertrophy  of  the  corpus  lu- 
teum. Then  rut  ceases.  If  the  corpus  luteum  be  removed,  rut  recurs. 
Moreover  Kleinhans  and  Schenk  showed  that  extirpation  of  the  corpus  luteum 
alone  does  not  lead  to  interruption  of  pregnancy,  therefore  that  the  develop- 
ment of  the  fertilized  egg  is  not  dependent  on  corpus  luteum. 

Pregnancy  leads  to  profound  changes  in  the  maternal  organism.  Accord- 
ing to  Neumann  and  Hermann  lipoidemia  can  always  be  demonstrated. 
They  found  the  lipoidemia  also  after  castration  and  in  the  climacteric  period. 
I  would  refer  it  especially  to  the  cessation  of  the  activities  of  the  follicular 
apparatus.  Further,  during  pregnancy,  are  found  signs  of  a  heightened 
excitability  of  the  vegetative  nervous  system.  L.  Pollak  could  show  during 
pregnancy  heightened  glycosuric  action  of  adrenalin.  The  statement 
as  to  an  increased  adrenolinemia  in  pregnant  women  {Neu)  could  not  be 
corroborated  by  Neuhauer  and  Novak. 

Very  commonly  in  the  latter  stages  of  pregnancy  is  found  a  neutro- 
philic hyperleucocytosis.  Further  the  temperature  is  placed  at  a  higher 
level,  and  also  the  blood-pressure  and  the  pulse  rate  are  higher. 

Also  investigations  on  the  metabolism  have  shown  that  there  are  pro- 
found alterations.  Falk  and  Hesky,  and  Zangemeister  found  relative  in- 
crease in  the  ammoniacal  nitrogen,  Leersum,  Rebaudi,  and  Falk  and  Hesky 
found  increase  in  the  amino  acids,  the  authors  last-named  also  an  increase  in 
the  polypeptid  nitrogen,  and  Salamon  and  Saxl  an  increase  in  the  elimina- 


378  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

tion  of  ox}'proteinic  acid.  The  tendency  of  pregnant  women  to  alimentary 
glycosuria  and  alimentary  levulosuria  is  well  known.  Lately  Novak  and 
Forges  have  discovered  a  tendency  toward  ketonuria.  The  cause  of  these 
metabolic  alterations  is  seen  by  most  of  the  authors  cited  in  a  disturbance  of 
the  function  of  the  liver,  from  which  they  have  inferred  degenerative  proc- 
esses in  that  organ.  It  would,  however,  be  remarkable  if  a  physiological 
process  such  as  pregnancy  should  regularly  lead  to  such  severe  disturbances; 
I  would  regard  as  the  cause  of  these  metabolic  disturbances  only  an  in- 
crease in  the  irritability  of  the  liver,  which  is  a  partial  phenomena  of  the 
increased  vitality  of  the  whole  organism. 

It  is  very  noteworthy  that  numerous  symptoms  point  to  an  increased 
function  of  almost  the  whole  ductless  glandular  system.  Certain  of  the 
previously  mentioned  symptoms  may  be  referred  with  some  probability 
to  an  energetic  activity  of  the  chromaffin  tissue;  the  regular  occurrence  of 
iron-free  pigment  perhaps  points  also  to  an  increased  adrenalin  consump- 
tion.^ As  is  known  such  pigmentations  develop  along  the  linea  alba,  at  the 
navel,  on  the  perineum,  on  the  labia  majora,  on  the  areolae  of  the  nipples, 
and  on  the  face  (chloasma  uterinum).  Very  noteworthy  is  the  occurrence 
of  abnormal  hairiness,  as  Halban  first  pointed  out.  Especially  distinct  is 
the  increased  growth  of  a  previously  existing  rudiment  of  the  beard.  Halban 
cites  a  very  interesting  case  of  Sloe  urn's.  A  woman  carried  three  children 
normally  and  also  had  an  abortion  at  the  sixth  or  eighth  week.  In  each 
pregnancy  the  beard  grew  on  the  cheeks  and  chin.  But  also  the  downy 
hair  on  the  entire  body,  especially  on  the  abdomen  and  on  the  linea  alba, 
grew  stronger  during  pregnancy.  These  hairs  fell  out  again  after  the  labor. 
Halhan  could  even  demonstrate  the  increased  growth  tendencies  of  the  hair 
in  animal  experiment.  After  shaving  of  the  abdomina  of  pregnant  animals 
the  hair  grows  faster  there  than  on  the  abdomina  of  nonpregnant  animals 
similarly  treated.  He  refers  these  anomalies  in  the  hairiness  to  the  internal 
secretory  activity  of  the  chorionic  epithelium;  it  would  also  be  likely,  how- 
ever, that  this  comes  into  relationship  with  the  h^-perplasia  of  the  suprarenal 
cortex  that  occurs  in  pregnancy,  as  is  pointed  out  by  Glynn.  This  hyper- 
plasia of  the  suprarenal  glands  has  been  demonstrated  by  v.  Haberer  and 
Stoerck. 

I  would  attribute  especial  value  to  the  fact  that  during  pregnancy  the 
interstitial  glands  develop  enormously.  This  fact  shows  that  also  in  the 
sexual  glands  of  the  female  there  is  a  certain  independence  of  the  function 
of  the  interstitial  glands  from  that  of  the  generative  glands.  While  the 
activity  of  the  follicular  apparatus  becomes  inhibited,  the  interstitial  glands 
show  histological  signs  of  an  increased  activity.  According  to  my  view  the 
clinical  symptoms  correspond  to  those  of  the  histological  finding.     As  I 

1  See  the  hypothesis  as  to  the  genesis  of  the  pigmentation  in  the  chapter  on  the  suprarenal 
apparatus. 


THE    GENERATIVE    APPARATUS  379 

already  emphasized  in  the  article  on  ductless  gland  diseases  in  Mohr-Stae- 
helins  handbook  (Vol.  IV),  I  cannot  subscribe  to  the  opinion  upheld 
especially  by  Tandler  and  Grosz  that  during  pregnancy  the  "internal  secre- 
tory" activity  of  the  ovary  is  inhibited  by  the  persistence  of  the  corpus 
luteum.  By  "internal  secretory"  activity  is  understood  by  these  authors  a 
function  that  in  fact  can  only  depend  on  the  interstitial  glands.  Against 
an  inhibition  of  the  interstitial  glands  speaks,  however,  the  fact  that  during 
pregnancy  the  secondary  sexual  characters  throughout  do  not  retrogress, 
and  on  the  contrary  there  is  found,  in  agreement  with  histological  findings, 
strong  accentuation  of  them.  Entirely  especial,  however,  are  the  views 
concerning  the  relation  of  the  sexual  glands  to  the  hypophysis,  which  had 
led  to  the  rapid  entrance  into  the  literature  of  what  I  consider  an  incorrect 
view.     Therefore  I  must  enter  into  this  question  more  in  detail. 

The  hypophysis  in  woman  during  pregnancy  enlarges  considerably. 
Its  weight  can  rise  to  two  and  one-half  times  as  much  as  normal.  Enlarge- 
ment of  the  anterior  lobes  is  exclusively  responsible  for  this  increase  in  weight; 
this  lobe  becomes  more  juicy  and  essentially  softer.  It  shows  the  occurrence 
of  enormous  numbers  of  pregnancy  cells,  which  develop  from  the  so-called 
chief-cells.  In  the  later  stages  of  pregnancy  more  than  four-fifths  of  the  organ 
may  consist  of  the  new  formed  cells.  Comte,  and  Launois  and  Moulon  first 
pointed  out  this  enlargement  of  the  hypophysis,  and  Erdheim  and  Stumme, 
whose  exposition  I  follow,  carefully  studied  these  alterations  in  a  great  num- 
ber of  cases.  Then  enlargement  of  the  hypophysis  during  pregnancy  is  some- 
times so  considerable  that  in  rare  cases  even  a  pressure-action  on  the  chiasma 
seems  to  be  possible,  v.  Reuss  described  repeated  temporary  blindness  dur- 
ing pregnancy,  while  Bellinzona  and  Tritondani  report  bilateral  narrow- 
ing of  the  visual  field.  Actually  there  exist  a  series  of  manifestations  that 
point  to  an  increase  in  function  of  the  hypophysis  during  pregnancy.  To 
these  may  belong  the  osteophyte  formations  on  the  internal  surface  of  the 
skull  that  are  associated  with  marked  hyperemia  of  the  dura.  In  addi- 
tion they  are  found  also  on  the  upper  jaw,  on  the  nose,  and  on  the  frontal  and 
parietal  bones  (Manau),  further  the  development  of  substance  devoid  of 
calcium  in  the  pelvis.  Breus  and  Kolisko  observed  increase  of  the  growth 
of  the  pelvis  during  pregnancy.  Tandler  and  Grosz  point  out  that  in  gravid 
persons  there  is  a  coarsening  of  the  facial  features,  especially  of  the  soft 
parts  of  the  nose,  lips,  and  moreover  that  a  thickening  of  the  hands  is  not 
rare,  manifestations  that  remind  one  of  a  slight  grade  of  acromegaly.  I 
refer  in  the  chapter  on  the  hypophysis  to  the  case  of  Marek,  in  which  we 
can  indeed  speak  of  a  transitory  forme  fruste  of  acromegaly.  x\s  far  as  the 
growth  of  hair  on  the  linea  alba  is  concerned,  I  should  rather  ascribe  it  to 
the  hyperplastic  alterations  of  the  suprarenal  cortex.  Into  association  with 
increase  of  function  of  the  hypophysis  may  be  brought  also  the  observa- 
tion of  Halhan  that  in  youthful  persons  whose  epiphysial  junctures  are  not 


380  THE    DISEASES    OF    THE    SEXUAL    GLAXDS 

yet  fully  closed,  the  growth  can  proceed  in  fits  and  starts  during  pregnancy. 
I  shall  refer  to  this  later. 

We  see  therefore  that  in  pregnancy  an  increase  of  the  function  of  the  hypo- 
physis is  associated  with  an  increase  of  function  of  the  interstitial  glands,  as  is 
also  the  case  in  acromegaly.  There  remains  only  one  point  that  also  seems 
very  much  to  support  the  view  of  Tandler  and  Grosz.  Tandler  and  Grosz  con- 
cerned themselves  with  the  observation  that  the  extirpation  of  the  ovaries, 
hence  a  removal  of  the  internal  secretory  activity  of  these  organs,  leads  to  en- 
largement of  the  hypophysis,  and  they  thus  regard  the  cause  of  the  tall  growth 
in  the  castrated  to  an  increase  in  the  function  of  the  hypophysis.  Fischer 
first  reported  that  in  capons  and  castrated  male  cattle  the  hypophysis  is  often 
twice  as  large  as  in  cocks  and  uncastrated  male  cattle.  Moreover,  Jutaka 
Kon  states  that  in  eight  castrated  women  the  hypophysis  was  found  enlarged 
and  rather  heavy.  The  enlargement  affected  the  glandular  part  alone  and 
on  histological  examination  there  was  found  the  picture  of  true  hyper- 
trophy. Finally  Tandler  and  Grosz  several  times  observed  a  strikingly 
large  sella  turcica  in  "skopzen."  [Seep.  391.]  So  far  as  the  findings  in  the 
hypophyses  of  castrated  animals  is  concerned,  there  is  found,  however,  the 
statement  that  manifestations  of  an  apparently  degenerative  kind  (vacuole 
formation)  are  often  observed.  I  am  very  sceptical  with  regard  to  the  finding 
of  Jutaka  Kon.  At  least  one  cannot  draw  from  it  the  inference  as  to  an  in- 
crease of  function  of  the  hypophysis,  for  nobody  would  state  that  symptoms 
occur  in  castrated  women  that  indicate  such  an  increase.  In  male  late 
castrates  may  be  observed  such  an  enlargement  of  the  sella  turcica,  as  in  one 
of  the  cases  I  reported  (castration  in  the  twenty-sixth  year  of  life) ,  or  in  the 
case  of  Rieger  (epistolatory  communication).  Further  Tandler  and  Grosz 
have  already  stated  that  no  enlargement  of  the  sella  was  found,  and  further 
on  I  shall  report  four  cases  of  eunuchoidism,  in  which  the  sella  was  found  to 
be  normal  in  size  or  strikingly  small.  Finally  as  far  as  the  tallness  of  enunchs 
and  eunuchoids  is  concerned,  I  would  refer  it  not  to  an  increase  in  function 
of  the  hypophysis,  but  to  a  persistence  of  the  epiphysial  junctures.  As 
we  have  seen  in  the  chapter  on  the  hypophysis  early  acromegaly  does  not 
always  lead  to  tallness,  also  not  when  the  epiphysial  junctures  have  not 
closed  prematurely.  Xor  are  there  to  be  found  in  eunuchs  or  in  eunuchoids 
any  other  signs  of  a  hyperfunction  or  an  increased  function  of  the  hypo- 
physis; I  call  to  mind  only  the  so  characteristic  behavior  of  the  carbohydrate 
metabolism  in  acromegaly.  The  view  of  Launois  and  Roy  that  when  the 
epiphysial  junctures  are  open,  functional  increase  of  the  hypophysis  leads 
to  tallness  or  to  gigantism,  and  when  closed,  to  acromegaly  is  to  my  mind  as 
untenable  as  the  opinion  that  falling  away  of  the  sexual  glands  produces  in- 
crease of  function  of  the  hypophysis.  If  we  follow  both  views  to  their  ulti- 
mate consequences,  we  arrive  at  the  postulate  that  castration  after 
epiphysial  closure  must  call  forth  acromegalic  manifestations,  as  is  evidently 


THE    GENERATIVE    APPARATUS  38 1 

not  the  case.  And  I  believe  therefore  that  Halban^s  symptom  of  increase  of 
growth  in  youthful  gravida  does  not  depend  so  much  on  increase  of  hypo- 
physial function  but  rather  much  more  on  the  periodically  increased  vitality 
of  the  whole  organism  when  the  epiphysial  junctures  are  open. 

Let  us  now  return  to  the  behavior  of  the  ductless  glandular  apparatus  in 
pregnancy.  I  must  here  mention  the  fact  known  already  in  antiquity  that 
during  pregnancy  there  is  increase  in  volume  of  the  thyroid  gland.  There 
develops  a  parenchymatous  struma  that  feels  soft  on  palpation.  There  is 
indeed  no  doubt  that  this  increase  in  volume  is  associated  with  a  slight  in- 
crease in  function,  that  is  even  a  partial  phenomenon  of  the  increased 
vitality. 

An  increase  of  function  of  the  parathyroids  and  of  the  pancreas  can  be 
inferred  by  us  only  indirectly,  from  the  fact  that  the  latent  insufhciency  of 
these  glands  tends  to  be  manifest  during  this  period;  we  have  grounds  for 
assuming  that  this  occurs  as  a  consequence  of  increased  demands  and  there- 
fore that  normally  the  function  of  these  ductless  glands  is  increased. 

We  will  now  describe  the  changes  undergone  during  pregnancy  by  the 
mammary  glands.  First  of  all  I  will  make  some  remarks  as  to  their  devel- 
opment. Halban,  whose  important  works  we  have  to  thank  for  our  informa- 
tion, distinguishes  four  periods  of  growth  impulse  separated  in  point  of  time. 
The  first  falls  about  in  the  time  between  the  eighth  and  ninth  lunar  months 
[of  embryonal  life].  The  second  occurs  at  the  time  of  puberty,  the  third 
always  recurs  at  the  premenstrual  periods,  and  the  fourth,  especially  inten- 
sive, occurs  during  pregnancy.  The  ovaries  constitute  the  trophic  center  for 
the  first  three  growth  impulses.  This  may  already  be  seen  by  the  fact  that 
in  disturbances  in  the  development  of  the  ovaries  the  breasts  too  remain 
undeveloped  (Foges).  The  growth  impulse  during  puberty  leads  as  is  known 
to  a  noticeable  development  of  the  glandular  parenchyma.  The  growth  im- 
pulse in  the  premenstrual  periods  can  in  rare  cases  be  so  strong  that  in  virginal 
individuals  colostrum  may  be  secreted,  and  later,  during  the  menstruation, 
milk  may  appear  {Scanzoni,  Gauthier).  The  most  intensive  impulse  of 
growth  occurs  during  pregnancy.  The  breasts  swell  and  toward  the  end 
of  pregnancy  may  yield  colostrum  on  expression.  There  is  no  doubt  but 
that  this  impulse  for  growth  is  set  free  by  hormones.  This  is  shown  by  ob- 
servations on  the  Siamese  twins,  Blazek;  when  the  one  became  pregnant  the 
breasts  of  the  other  swelled  also,  and  after  confinement,  secretion  of  milk 
occurred  in  both  {Schauta) ;  Grigori  and  M.  Cristea  could  make  the  same 
observation  on  parabiotic  animals.  For  the  hormone  theory  speaks  also 
the  observation  of  Rihhert  that  transplanted  mamm'se  secrete  milk  after 
birth.  The  ovaries  are  not  necessary  for  the  pregnancy-hyperplasia  of 
the  mammae,  as  also  in  spite  of  castration  undertaken  in  the  early  stages 
of  pregnancy,  the  development  of  the  breasts  proceeds  in  a  normal  manner, 
and  the  women  are  able  to  suckle  their  children.     Mainzer  has  collected 


382  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

sixteen  such  cases  from  the  Hterature  and  Halhan  has  added  three  more. 
It  looks  very  much  now  as  though  the  removal  of  the  ovary  later  exercises 
a  favorable  influence  on  milk-production,  as  breeders  state  that  castrated 
cows  yield  abundant  milk.  Noteworthy  in  this  respect  is  the  case  of  Foges. 
After  a  labor  a  woman  experienced  a  secretion  of  milk  for  seventeen  years. 
During  this  time  constant  amenorrhea  existed.  After  seventeen  years  men- 
struation a  new  conception  occurred.  After  the  labor  the  milk-secretion 
continued  again  for  six  years. 

Milk  usually  comes  on  two  or  four  days  after  labor.  This  whether  the 
birth  takes  place  at  normal  time  or  whether  there  has  been  a  miscarriage. 
Secretion  of  milk  has  even  been  observed  after  an  abortion  as  early  as  the 
second  month  of  pregnancy.  As  the  pregnancy-hyperplasia  of  the  breasts 
is  independent  of  the  ovaries,  Starling  and  Lane-Clay pon  have  regarded  the 
fetus  as  the  source  of  the  mammary  gland  hormone.  Actually  they  even 
succeeded  in  inducing  growth  of  the  mammary  glands  by  injection  of  ex- 
tract of  embryos  into  the  peritoneal  cavity  of  rabbits  that  had  not  yet  been 
covered.  Also  Biedel  and  Kbnigstein  lend  themselves  to  this  view,  as  has 
also  Fod  who  recently  on  the  ground  of  his  experiment  has  upheld  the 
opinion  that  the  mammary  glandular  hormone  was  not  specific  in  kind. 
Against  this,  Halhan  has  upheld  the  view  that  the  pregnancy-hyperplasia  of 
the  breasts  is  produced  by  a  hormone,  that  proceeds  from  the  chorionic 
epithelium  of  the  placenta.  Halban  bases  his  view  on  the  following  observa- 
tions. The  pregnancy-hyperplasia  of  the  breasts  can  still  develop  if 
the  fetus  has  been  dead  a  long  time  but  the  placenta  remains  living.  If, 
however,  the  placenta  too  dies,  the  further  development  of  the  mammary 
glands  ceases  and  milk  begins  to  flow.  Halhan  further  observed  two  casee  of 
cystic  mole,  in  which  secretion  of  milk  began  after  expulsion  of  the  mole. 
Halhan  sets  forth  that  the  chorionic  villi  develop  from  the  fertilized  egg 
and  in  spite  of  enormous  growth  until  the  end  of  pregnancy  undergo  but 
little  dift'erentiation.  By  the  copulation  of  spermatozoa  and  ovum  is  ex- 
plained the  fact  that  the  hormonopoietic  action  of  chorionic  epithelium  is 
stronger  than  that  of  the  ovum  alone.  Hardly  anything  can  be  objected 
against  Halhan's  clinical  observations.  On  the  contrary  it  seems  to  be  not 
refuted  that  also  from  the  fetus  may  mammary  glandular  hormones  proceed, 
as  indeed  the  chorionic  epithelium  may  live  without  fetus,  but  not  the  fetus 
without  chorionic  epithelium.  Hence  it  seems  to  me  that  the  views  of 
Halhan  and  of  Starling  are  not  irreconcilable. 

Yet  a  few  remarks  concerning  the  onflow  ["  Einschiessen,"  literally  a 
shooting  in]  of  the  milk,  which,  as  previously  mentioned,  usually  occurs  on  the 
second  to  fourth  day  after  birlh.  It  was  formerly  regarded  that  the  cause  of 
the  onflow  was  the  act  of  suckling,  but  Halhan  has  pointed  out  that  suckling 
during  pregnancy  may  indeed  induce  the  secretion  of  colostrum,  but  never 
calls  forth  the  production  of  milk  (cases  of  Duval  and  of  Hildebrand).     The 


THE    GENERATIVE    APPARATUS  383 

onflow  of  milk  also  occurs  in  cases  in  which  the  child  has  never  been  put  to 
the  breast.  On  the  other  hand  (apart  from  such  cases  as  the  case  of  Foges 
cited  above)  the  act  of  suckling  or  of  drawing  off  the  milk  is  requisite  for 
the  continuance  of  the  milk-secretion.  From  a  series  of  clinical  observa- 
tions Halhan  draws  the  conclusion  that  the  onflow  of  milk  always  coincides 
with  the  removal  or  the  death  of  the  placenta.  Again,  the  extirpation  of  the 
ovaries  at  a  time  other  than  during  pregnancy  may  increase  the  existing 
secretion  of  milk,  while,  as  is  known,  the  occurrence  of  menstruation  during 
lactation  inhibits  the  secretion  of  milk,  and  indeed  in  the  premenstrual 
period,  and  also  that  amount  of  its  solid  constituents,  especially  the  casein, 
the  fat,  and  the  salts,  are  diminished  {N .  Davis).  Indeed  even  at  the  be- 
ginning of  the  chmacteric  there  may  exist  for  a  time  with  the  introduction  of 
the  ovarian  function  painful  swelling  of  the  breasts  and  excretion  of  milk. 
Halhan  reports  such  a  case.  Halhan  therefore  concludes  that  the  ovary  is 
growth-inducing  and  secretion-inhibitory  on  the  mammary  glands,  just  as 
is  the  placenta,  only  less  so. 

Finally  there  remains  to  be  mentioned  the  pregnancy  reactions  of  the 
fetus  described  by  Halhan.  The  uteri  of  new-born  girls  regularly  show 
considerable  hyperemia  and  histological  alterations  of  the  mucous  mem- 
brane that  bear  great  similarity  to  those  of  menstruation.  There  may  even 
occur  genital  hemorrhage,  that  have  nothing  to  do  with  menstruatio  praecox, 
as  the  latter  usually  set  in  much  later,  at  a  time  that  ovaries  haye  shown  signs 
of  maturity.  The  uterus  of  the  new-born  girls  shows  almost  always  a  slight 
involution  that  is  usually  completed  three  weeks  postpartum.  Moreover, 
the  mammary  glands  of  new-born  girls  and  boys  show  signs  of  epithelial 
proliferation,  indeed,  even  the  secretion  of  colostrum  (witch's  milk).  Fur- 
ther, the  blood  shows  a  slight  grade  of  hyperleucocytosis  and  increased 
coagulability.  Finally  the  prostate  of  the  new-born  boy  shows  a  slight 
hyperplasia,  which  is  then  affected  by  involution.  Halhan  correctly  brings 
all  these  manifestations  in  analogy  with  the  pregnancy-reactions  and  ascribes 
them  to  the  hormonopoietic  function  of  the  chorionic  epithelium. 

After  labor,  as  is  known,  there  occurs  in  the  mother  a  rapid  retrogression 
of  all  the  profound  alterations  just  described.  The  neutrophilic  hyperleuco- 
cytoses  give  place  to  a  leucopenia  with  mononucleosis,  the  tachycardia 
temporarily  to  a  bradycardia.  With  the  onset  of  the  milk,  numerous 
eosinophilic  cells  make  their  appearance  in  the  blood  {Blumenthal) .  Accord- 
ing to  Novak  and  J etter  there  are  found  in  the  early  puerperium  different 
irritative  symptoms  of  the  entire  vegetative  system;  then  the  signs  of  an 
increase  in  the  functions  of  the  ductless  glandular  system  gradually  vanish. 

Surveying  now  the  alterations  described,  which  take  place  in  the  organ- 
ism of  pregnant  women,  we  find  that  they  are  entirely  analogous  to  those 
which  occur  in  the  premenstrual  period,  while  those  of  the  puerperium  are 
analogous  to  those  of  the  menstrual  period.     As  is  known,  labor  takes  place  at 


384  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

the  menstrual  term.  Hence  seems  justified  the  dictum  of  W.  H.  Freund 
that  "labor  is  a  menstruation,  in  which  a  fully  developed  egg  is  extruded." 
While,  however,  the  phenomena  of  the  premenstrual  period  proceed  from 
the  ovary,  there  can  be  no  doubt  at  all  that  the  similar,  but  potentized, 
manifestations  of  pregnancy  proceed  from  the  developed  egg.  It  therefore 
seems  to  me  that  the  conclusion  lies  at  hand  that  all  the  manifestations  of 
premenstrual  period  are  set  free  by  the  maturing  follicle,  which  only  renders 
intelligible  the  fact  that  the  extirpation  of  the  ovaries  during  pregnancy  has 
no  influence  on  this  phenomenon,  as  the  maturing  ovum  no  longer  is  found 
in  the  ovary,  but  in  the  uterus.  From  this  we  see  that  if  we  ascribe  to 
women  an  interstitial  gland,  it  can  have  very  little  to  do  with  the  phenomenon 
during  pregnancy.  It  takes  part  in  hyperplasia  and  in  increase  in  function 
only  in  the  same  manner  as  do  the  other  ductless  glands,  and  the  stronger 
emphasis  of  many  of  the  so-called  sexual  characters  may  stand  in  connection 
with  it.  The  most  important  prevailing  alterations  of  pregnancy  are  at  all 
events  independent  of  it. 

At  the  climacteric  the  interstitial  glands  show  certain  regressive  changes; 
they  are,  however,  retained  in  part,  while  ovulation  ceases  entirely.  The 
lipoidemias  that  Neumann  and  Hermann  observed  in  postclimacteric  women 
are  in  my  opinion  to  be  referred  to  the  falling  out  of  the  function  of  the  fol- 
licular apparatus.  As  is  known,  libido  may  be  retained  for  a  still  longer 
time.  The  function  of  the  sexual  glands  is  usually  associated  with  an  in- 
crease in  the  fatty  layer  of  the  abdomen  and  mammae.  As  is  known  there 
occur  during  the  transition  period  numerous  nervous  disturbances,  that 
point  to  extraordinary  changing  and  manifold  conditions  of  excitation 
in  the  vegetative  nerves.  Manifold  symptoms  of  a  psychical  hyperirrita- 
bility  are  added,  an  existing  hysteria  becomes  worse,  and  when  a  predisposi- 
tion to  a  psychosis  exists  this  may  develop  to  a  climacteric  psychosis,  which, 
however,  has  no  specific  character  {Kraft-Ehing). 

We  now  have  to  consider  the  question  as  to  whether  the  generative  ap- 
paratus in  man  too  possesses  an  internal  secretion.  We  have  already  seen 
that  there  are  clinical  observations  to  the  effect  that  the  function  of  the 
generative  apparatus  does  not  develop  (the  kryptochides  inguinales  of 
Variot),  while  the  interstitial  glands  and  with  them  also  the  masculine  habitus 
are  well  developed,  and  that  on  the  other  hand  similar  results  have  been 
brought  about  by  experiments.  It  would  now  be  proper  to  investigate 
whether  such  sterile  but  otherwise  masculine  individuals  possess  the  same 
libido  as  normal  individuals.  The  cardinal  point  is  the  fact  whether  the 
developmental  disturbance  sets  in  in  early  youth,  or  that  experimental  attack 
is  made  on  quite  young  animals.  For  experience  teaches  that  if  once  the 
generative  apparatus  has  been  fully  developed  and  has  functionated  normally 
then  also  after  complete  extirpation  of  the  sexual  glands  the  libido  can  be 
retained  for  a  long  time.     It  seems  to  me  important,  however,  that  also  in 


THE    GENERATIVE    APPARATUS  385 

such  cases  the  hbido  is  mostly  released  only  through  external  influences. 
On  the  whole  it  seems  to  me,  although  I  can  not  demonstrate  this  with 
certainty,  that  a  normally  strong  sexual  instinct  is  present  only  when  the 
function  of  the  generative  gland  is  normal,  and  in  this  circumstance  speaks 
for  the  hormonopoietic  function  of  the  generative  glands. 

The  known  stimulating  action  on  the  central  nervous  system,  which 
expresses  itself  in  tendency  to  movement  and  in  a  heightened  muscular 
tonus,  which  comes  to  expression  also  in  a  spiritual  sense  in  higher  creative 
activities,  and  which  characterizes  especially  the  period  of  "Sturm  and 
Drang,"  I  would  refer  more  to  the  hormonopoietic  activity  of  the  generative 
glands.  What  has  been  done  experimentally  on  this  question  does  not  lend 
itself  to  the  support  of  this  view.  On  the  whole  the  numerous  reports  as  to 
the  stimulating  action  of  testicular  extract  and  of  spermin  Poehl  have  not 
been  written  with  the  necessary  critique;  the  careful  investigations  oiZoth  and 
Pregl,  which  showed  an  increase  of  the  muscular  capacity,  were  made  with 
extracts  of  whole  testicle,  so  we  are  unable  to  say  what  part  the  generative 
glands  had  in  producing  the  effect. 

While  in  man  the  function  of  the  generative  glands  is  a  more  continuous 
one,  there  exist  in  the  most  of  male  animals  the  same  cycle  as  in  the  fe- 
males. As  is  known,  the  complete  extirpation  of  the  sexual  glands  prevents 
a  recurrence  of  rut.  Although  in  some  cases  the  wave  of  rut  remains  for 
some  time  longer,  I  would  not  lay  much  stress  on  this  fact  as  Halban  does. 
Here  also  must  we  consider  that  the  organism  had  been  accustomed  to  the 
rut-wave  for  a  long  time.  As  certain  cohabitation  experiments  show,  how- 
ever, it  is  possible  that  it  is  promoted  psychically  by  the  rutting  female.  I 
believe  also  here  the  question  permits  of  discussion  as  to  whether  many 
of  the  rut  phenomena  usually  grouped  with  secondary  sexual  characters, 
that  are  necessary  for  the  act  of  copulation,  as  for  instance,  the  hypertrophy 
of  the  arm  musculature  and  the  thumb  callosities  in  frogs,  are  set  free  by 
the  generative  glands.  I  have  been  unable  to  find  any  experimental  inves- 
tigations that  help  to  clear  up  this  question. 

I.  THE  MALFORMATIONS 

It  is  not  my  intention  to  enter  into  a  comprehensive  exposition  of  the 
malformations  accruing  to  the  sexual  glands.  I  shall  only  choose  those 
types  that  seem  to  me  important  for  the  discussion  of  the  problems  stated 
above. 

I.  Aplasia  of  the  Sexual  Glands 

Halban  has  collected  from  the  literature  the  reports  of  cases  of  con- 
genital amorphia  or  aplasia  of  the  ovaries.  They  all  come  from  the  older 
literature,  so  that  Tandler  and  others  have  expressed  doubt  as  to  the  exact- 

25 


386  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

ness  of  the  observations.  It  is  true  that  this  doubt  does  not  extend  to  the 
observations  on  anorchia  that  were  made  on  boys  shortly  after  birth.  In  such 
cases  are  always  found  also  anomalies  of  the  internal  genitalia — anomalies 
such  as  lack  of  the  epididymis  or  of  the  funiculi  spermatid  or  the  vesiculae  semi- 
nales.  When,  however,  we  hear  in  many  of  the  observations  in  old  literature 
as  to  aplasia  of  the  sexual  glands  that  the  external  and  internal  genitalia  were 
quite  well  developed,  or  that  in  the  male  individual  a  beard  was  present, 
such  a  doubt  is  well  justified.  It  is  at  all  events  very  striking  that  no  such 
observations  have  been  made  in  the  last  decade,  although  the  number  of 
sections  has  enormously  increased.  From  the  observations  on  anorchia  in 
new-born  children  the  most  that  can  be  mentioned  is  that  also  without 
sexual  glands  there  is  possible  a  development,  if  only  a  disturbed  develop- 
ment, of  the  male  or  female  accessory  genital  apparatus,  and  perhaps  other 
characteristics  of  the  male  sex. 

Also  the  observations  that  Landau  and  Peck  publish  concerning  the  exist- 
ence of  individuals  of  a  neutral  sex  do  not  seem  to  me  to  be  free  from  objec- 
tions. I  quote  the  following  two  cases  that  Peck  regarded  as  especially 
important.  In  the  case  of  v.  Sivinarski-Pfannenstiel  there  was  a  fifty-five- 
year-old  unmarried  "woman,''  who  had  never  menstruated.  The  general 
habitus  was  masculine,  the  clitoris  3  cm.  long,  both  ovaries  were  considerably 
enlarged,  the  superficies  smooth,  no  corpora  lutea  were  to  be  seen,  and  on 
microscopical  examination  the  ovaries  were  found  to  be  entirely  "parenchy- 
maless."  The  internal  genitalia  were  those  of  the  female.  The  case  of 
Hou'itz  was  that  of  a  forty-nine-year-old  unmarried  "woman."  The  hairi- 
ness and  form  of  the  pelvis  were  masculine;  the  large  and  small  labia  were 
present,  the  clitoris  was  6  cm.  long  and  2  cm.  thick.  The  urogenital  sinus 
was  smooth,  and  on  its  floor  was  found  an  opening  through  which  one  could 
pass  a  thin  sound  into  the  7  cm.  long  vagina.  Between  the  thirtieth  and  for- 
tieth years  of  life  blood  issued  from  the  vagina  at  intervals  of  one  to  several 
years.  At  the  site  of  the  ovaries  on  each  side  was  to  be  found  a  body  of  the 
shape  and  size  of  an  almond.  There  was  no  follicle  formation  in  the  ovaries, 
and  the  stroma  was  strikingly  hard.  In  this  case  which  had  come  to  advanced 
age  one  could  not  say  with  certainty  that  the  follicular  apparatus  had  always 
been  entirely  absent.  The  absence  of  menstruation  does  not  allow  of  the 
statement  that  at  least  for  a  time  there  did  not  exist  a  tendency  [start, 
Ansatz]  for  menstruation.  Also  statements  to  the  proportioning  of  the  body 
are  not  given.  Finally  an  examination  of  the  suprarenal  cortex  in  such  cases 
would  be  very  desirable.  It  seems  to  me  therefore  that  such  cases  should  not 
enter  into  our  discussion. 

2.  Hermaphroditism 

We  distinguish  a  Jicrmaphroditismus  veriis  and  IicrmapJiroditismiis  spurius 
or  pscudohcrma pJiroditism .     Cases  of  hermaphroditismus  verus,  in  which  ova- 


HERMAPHRODITISM  387 

ries  as  well  as  testicles  are  capable  of  functionating,  are  as  yet  unknown 
in  man.  But  there  are  cases  of  so-called  ovotestis;  I  will  cite  some  examples. 
A  case  of  Salen  was  that  of  a  forty-three-year-old  "woman."  Menstruation 
had  existed  since  the  seventeenth  year,  the  clitoris  was  5  cm.  long,  the  vagina 
6  cm.  long,  the  labia  majora  were  of  normal  development,  the  habitus  was 
feminine.  The  ovotestes  show  in  the  ovarian  part  Graafian  follicles  and 
t^^ical  ovules,  in  the  testicular  part  seminal  tubules,  Leydig's  interstitial  cells, 
but  no  sperm.  The  case  of  Simon  was  that  of  a  twenty-year-old  "man." 
The  individual  felt  as  if  he  were  a  man.  The  sexual  inclination  was  mascu- 
line. ^Menstruation  had  existed  for  three  years,  the  secondary  sexual 
characters  were  mixed,  with  the  feminine  predominant.  The  labia  majora 
were  well  developed,  the  penis  was  6.5  cm.  long,  the  glans  was  not  perforated. 
There  were  found  tubes,  parovaries,  and  ligamenta  lata;  vasa  deferentia  and 
epididymis  were  without  connection  with  the  testicular  part  of  the  ovatestis. 
In  the  latter  were  found  typical  sexual  glandular  tissue  of  both  sexes,  but  no 
sure  signs  of  function. 

In  pseudohermaphroditism  there  are  found  sexual  glands  of  one  sex  and 
the  sexual  characters  of  the  other.  We  distinguish  pseiidohermaphroditismus 
internus,  if  only  the  internal  sexual  passages  of  the  other  sex  are  present, 
and  a  pseudohermaphroditismus  externiis,  if  only  the  external  sexual  passsagcs 
of  the  opposite  sex  are  present,  and  a  pseiidohermaphroditismiis  completus 
when  both  external  and  internal  sexual  passages  of  the  other  sex  are  present. 
Further,  according  to  the  prevalence  of  the  sexual  glands  a  pseudohermaphro- 
ditismus femininus  or  masculinns . 

As  an  example  of  the  pseudohermaphroditismus  completus  I  cite  the 
case  of  Heyn.  The  habitus  of  a  forty-six-year-old  individual  was  entirely 
feminine.  The  person  married  at  the  age  of  twenty-one  years,  sexual  inter- 
course was  entirely  normal  and  was  attended  with  orgasm  and  discharge. 
There  was  found  a  vaginal  cul-de-sac;  uterus,  ovaries,  prostate  were  absent. 
Testicles  were  present  on  both  sides. 

In  pseudohermaphroditism  are  found  all  conceivable  varieties.  There 
are  cases  of  somatic  pseudohermaphroditism  in  which  not  only  the  sexual 
organs  but  all  the  psychical  characteristics  of  the  other  sex  prevail,  c'. 
Neugehauer  has  collected  twenty-five  such  cases.  Further,  there  are  cases  in 
which  the  secondary  sexual  characters,  such  as  hairiness,  voice,  dimensioning 
of  the  body,  belong  partly  to  one  and  partly  to  the  other  sex.  and  there  are 
cases  in  which, the  sexual  glands  and  genitalia  belong  to  one,  the  secondary 
sexual  characters  to  the  other  sex  (pseudohermaphroditismus  secundarius, 
Halhan) . 

Finally  there  are  observations  concerning  unilateral  pseudohermaphro- 
ditism. In  man  so  far  as  is  known,  this  has  been  observed  in  a  very  rudi- 
mentary form  only.  Halhan  cites  cases  of  unilateral  development  of  the 
breasts  in  women.     There  are,  however,  numerous  such  observations  on 


388  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

the  part  of  zoologists.  Delbel  saw  butterflies  that  possessed  on  the  one  side 
an  ovary,  and  on  the  other  a  testicle,  and  in  which  one-half  of  the  body  was 
colored  like  that  of  a  female,  the  other  side  like  that  of  a  male.  I  further 
cite  the  known  observation  of  Weber.  A  finch  possessed  testicle  and  male 
plumage  on  one  side,  an  ovary  and  female  plumage  on  the  other. 

Let  us  now  survey  the  rich  material  of  facts,  from  which  I  have  chosen 
only  a  relatively  few  illustrative  examples,  but  examples  that  are  important, 
and  let  us  proceed  on  the  basis  of  these  to  enter  into  the  discussion  of  the 
problems  mentioned  above. 

Let  us  turn  first  to  the  relation  between  sexual  glands  and  the  secondary 
sexual  characters.  I  would  here  sketch  again,  in  outlines,  the  different 
views.  We  have  seen  that  in  this  respect  two  views  stand  bluntly  opposed 
to  each  other.  According  to  one  the  sexual  characters  exist  from  the  be- 
ginning, there  exists  a  male,  a  female,  and  hermaphroditic  predisposition, 
and  the  sexual  glands  exercise  only  a  protective  stimulus  on  the  development 
of  the  sexual  characters.  According  to  the  other,  it  is  the  sexual  glands 
alone  that  form  the  sexual  characters.  The  authors  that  adhere  to  the 
last  opinion,  show  that  indeed  already  in  the  first  embryonal  stages  there 
are  differences  to  be  observed  between  the  male  and  female  sex,  but  that 
the  sexual  glands  have  begun  to  develop  already  at  this  time  and  begin  to 
exercise  their  influence. 

It  will  be  seen  at  the  first  glance  that  multiplicity  of  the  phenomena  is 
not  explained  in  a  satisfactory  manner  by  the  last-named  assumption.  How 
shall  we  explain  the  coming  about  of  complete  hermaphroditism  in  which 
the  sexual  glands  of  one  sex  lead  to  the  development  of  the  sexual  characters 
of  the  other,  if  the  sexual  glands  exert  a  specific  sex-determining  formative 
stimuKis?  Even  less  explicable  according  to  this  hypothesis  is  the  occurrence 
of  unilateral  hermaphroditism.  In  this  connection,  no  matter  from  which 
point  of  view  we  regard  the  matter,  we  cannot  circumvent  the  opinion  of 
Halban.  For  this  opinion  speaks  also  the  circumstance  that  in  hermaphrodit- 
ism the  heterosexual  characters  are  enormously  developed  even  at  the  time 
of  puberty,  and  the  known  fact  that  unioval  twins  are  always  of  the  same 
sex.  Only  in  the  last  analysis  does  this  solution  meet  with  great  difiiculties. 
According  to  it  we  should  suppose  that  the  protective  influence  of  the 
sexual  glands  would  be  always  active  if  it  met  with  a  heterosexual  predispo- 
sition. According  to  this  we  would  expect  that  when  the  sexual  glands  are 
extirpated  in  a  not  yet  fully  developed  animal,  and  the  sexual  glands  of  the 
opposite  sex  are  implanted  in  this  animal,  the  original  predisposition  w^ould 
come  to  development  even  then.  Steinach  has  followed  this  method.  He 
implanted  ovaries  into  previously  castrated  young  males  of  guinea-pigs  and 
rats.  The  transplants  "took,"  and  not  only  the  interstitial  glands  de- 
veloped, but  also  the  primary  follicles,  to  large  follicles  with  normal  ova,  and 
there  occurred  in  entirely  normal  manner  the  formation  of  atretic  follicles 


HERMAPHRODITISM  389 

of  corpora  lutea.  In  these  animals  not  only  did  the  penis  cease  develop- 
ing, but  it  was  even  set  back  in  its  development.  If  a  tube  and  a  piece 
of  the  uterus  were  transplanted  with  the  ovary,  these  developed  to  mature 
organs.  Moreover,  there  came  about  an  enormous  development  of  the 
mammary  glands,  that  in  form  and  size  were  entirely  Hke  those  of  normal 
female,  and  indeed  even  exceeded  them  in  size.  Furthermore,  the  animals 
remained  behind  in  growth,  the  body  showed  entirely  the  proportioning  of 
the  female;  also  the  growth  of  hairs  and  the  layer  of  fat  showed  the  texture 
of  that  of  the  females,  and  there  was  a  reversal  of  the  psychical  sexual 
characters. 

If  Steinach's  experiments  were  to  receive  full  corroboration,  were  someone 
in  converse  manner  successful  in  bringing  to  previously  castrated  females  the 
male  sexual  characters  by  implantation  of  testicles,  we  would  have  to  agree 
that  they  would  stand  in  contradiction  to  Halhan's  view.  I  believe,  however, 
that  we  would  not  be  making  allowance  for  the  difficulty  of  the  problem,  if 
we  were  to  regard  it  as  entirely  solved  by  this  view;  for  Steinach's  experi- 
ments do  not  explain  the  occurrence  of  heterosexual  characters  in  the  pres- 
ence of  the  sexual  glands  of  the  other  sex.  The  observations  belonging  to 
this  problem  have  led  Biedl  to  assume  an  hermaphroditic  mapping-out 
[Anlage]  of  the  sexual  glands.  The  occurrence  of  heterogenous  sexual 
characters  is  explained  by  Biedl  by  his  supposing  that  the  internal  secretory 
part  of  the  sexual  glands  that  belongs  to  the  opposite  sex  gains  the  upper 
hand.  Biedl  thus  explains  the  occurrence  of  certain  masculine  characters 
in  old  women  after  the  menopause. 

On  cessation  of  the  activity  of  the  female  sexual  glands,  there  can  occur, 
according  to  Biedl,  a  reversal  of  the  sexual  characters  in  that  the  existent 
male  sexual  glands  continue  to  functionate.  I  would  here  agree  with 
Novak  in  not  considering  the  illustration  that  Biedl  employs  as  convinc- 
ing. The  occurrence  of  the  so-called  old  woman's  beard  is  not  a  male 
sexual  character.  Its  occurrence  is  explained  much  more  adequately  by 
Halban,  who  points  out  that  the  individual  sexual  characters  possess  very 
different  tendencies  to  growth  and  that  the  development  of  the  beard  in 
women  is  very  much  delayed.  In  the  same  manner  I  do  not  regard  the 
localization  of  the  deposits  of  fat  in  old  men  as  a  female  sexual  character, 
but  rather  as  the  sign  of  the  beginning  dissolution  of  the  activities  of  the 
sexual  glands,  only  as  the  suggestion  of  a  symptom  that  in  eunuchoidism  is 
exhibited  in  early  years  in  a  pronounced  manner. 

It  therefore  seems  to  me  that  the  only  possibility  is  to  look  for  the 
solution  of  the  problem  in  another  direction;  we  should  not  endeavor  to 
crowd  all  of  the  manifestations  into  one  of  the  views  set  forth,  but  should 
consider  the  question  as  to  whether  the  genesis  of  the  sexual  characters  is 
not  determined  by  a  number  of  factors.  We  cannot  discard  the  assump- 
tion of  a  preexistent  tendency  for  certain  sexual  characters  without  doing 


39©  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

away  with  the  problem  altogether.  Before  all,  however,  we  should  think  of 
the  possibility  that  the  sexual  glands  actually  give  off  the  formative  stimulus 
for  many  a  sexual  character,  especially  if  we  take  the  viewpoint  that  some  of 
the  sexual  characters  come  under  the  dominating  influence  of  the  interstitial 
glands,  others  under  those  of  the  generative  glands.  I  have  previously  set 
forth  that  if  we  ascribe  to  women  an  independent  function  of  the  interstitial 
and  the  generative  glands,  the  development  of  the  mammary  glands  seems  to 
stand  only  under  the  formative  stimulus  of  the  follicular  apparatus  or  of 
the  ovum.  From  this  standpoint  it  is  worthy  of  note  that  Steinach  in  his 
experiments  transplanted  not  only  the  interstitial  glands  but  also  the  follicu- 
lar apparatus.  We  can  readily  imagine  that  the  interstitial  glands  alike, 
whether  they  come  from  man  or  woman,  exercise  the  same  protective  stimulus 
on  certain  preexistent  masculine  or  feminine  sexual  characters;  but  no  one 
would  expect  the  same  action  from  the  masculine  as  from  the  feminine  gen- 
erative glands. 

Finally  we  should  think  of  the  possibilit)-  that  the  development  of  many 
of  the  sexual  characters  comes  entirely  or  partially  under  the  influence  of 
other  ductless  glands.  A  new  viewpoint  has  lately  opened  in  this  direction, 
a  viewpoint  that  also  seems  adapted  for  showing  the  occurrence  of  many 
a  heterosexual  character  in  a  new  light.  I  refer  to  those  observations  that 
were  described  in  detail  in  the  consideration  of  tumors  of  the  suprarenal 
cortex.  Women  who  have  developed  entirely  normally  up  to  or  beyond  the 
age  of  puberty  become,  on  the  development  of  such  a  tumor,  amenorrheic; 
the  uterus  atrophies,  and  there  develops  a  hypertrichosis.  ]\Iustache  and 
beard  grow,  and  hairs  on  the  trunk  become  abundant;  in  short,  the  distri- 
bution of  hair  assumes  quite  the  masculine  type.  The  supposition  that  this 
heterosexual  hairiness  is  to  be  referred  to  a  hyperfunction  of  the  suprarenal 
cortex  is  very  probable,  suggesting  the  thought  that  also  in  the  virile  type 
of  hairiness  that  is  observed  in  acromegalic  women,  or  even  in  normal  women 
during  pregnancy  there  is  the  same  cause — for  hyperplasia  of  the  suprarenal 
cortex  is  observed  in  both  conditions. 

Why,  however,  do  we  find,  in  those  cases  in  which  the  suprarenal  tumor 
develops  in  earliest  youth,  a  premature  development  of  the  genitalia  with 
marked  accentuation  of  the  sexual  characters  without  reversal  to  the  hetero- 
sexual type,  while,  when  it  occurs  in  women  who  are  already  matured,  the 
activity  of  the  sexual  glands  fails?  In  explaining  this  fact  I  would  refer  once 
more  to  the  relations  in  acromegaly.  Here,  in  addition  to  marked  accen- 
tuation of  many  sexual  characters,  in  addition  to  the  masculine  type,  we 
find  either,  mostly  only  temporary,  increase  of  the  activity  of  the  genera- 
tive gland  (even  with  secretion  of  colostrum)  or,  what  is  more  frequently  the 
case,  the  failure  of  this  from  the  beginning.  In  this  there  seems  to  me  to 
lie  an  analogy  with  the  behavior  of  the  generative  glands  in  tumors  of  the 
suprarenal  cortex;  we  may  assume  that  hyperfunction  of  the  suprarenal 


EUNUCHS  391 

cortex  always  leads  to  a  marked  development  of  the  hairiness  on  the  trunk, 
but  that  an  increase  of  the  activity  of  the  generative  glands  enters  in  only 
when  there  is  an  especial  vitahty  of  these  glands,  while  in  the  cases  in  which 
vitality  fails,  there  is  rapid  exhaustion.  In  the  very  strong  impulses  in 
childhood  there  would  come  about  a  pronounced  increase  (premature  de- 
velopment), and  in  already  matured  individuals  an  exhaustion.  In  acro- 
megaly, in  which  this  impulse  is  very  much  less  feeble,  a  temporary  increase 
of  function  may  first  occur,  even  in  late  years,  although  in  most  cases  the 
exhaustion  appears  in  the  foreground  already  from  the  beginning. 

These  observations  and  convictions  ascribe  to  the  suprarenal  cortex 
an  important  trophic  influence  on  a  very  important  sexual  character,  namely, 
the  hairiness.  This  supposition  finds  a  certain  support  in  embryology  and 
histology.  Let  us  recollect  that  the  suprarenal  glands  as  well  as  the  inter- 
stitial glands  are  of  mesodermal  origin,  that  both  proceed  from  immediately 
contiguous  parts  of  the  celom,  and  that  the  histological  picture  of  cortical 
cells  and  the  interstitial  cells  present  a  great  similarity.  Also  Glynn  inclines 
to  the  assumption  that  the  suprarenal  cortex  is  a  trophic  center  for  the  growth 
of  beard  and  the  hairiness  on  the  body,  and  beheves  that  we  should  properly 
expect  that  in  man  the  suprarenal  cortex  is  better  developed  than  in  woman. 
As  is  known,  this  is  really  not  the  case.  I  would  not,  howcAxr,  ascribe  any 
great  significance  to  this  absence  of  better  development  in  man.  As  we  can- 
not quite  discard  the  assumption  of  a  masculine  or  a  feminine  predisposition 
[Anlage]  for  the  body,  it  is  explicable  that  ^vith  normal  impulses  the  mascu- 
line or  feminine  type  of  hair  distribution  will  exist.  When,  however,  the 
impulse  is  considerably  increased,  then  the  \drile  t^'pe  in  man  is  potentized, 
while  in  women  the  virile  type  is  approached  or  attained.  Even  under 
physiological  conditions,  namely,  in  pregnancy,  is  there  an  approach  to 
the  virile  t}^e.  This  idea  also  includes  the  explanation  of  why  in  pseudo- 
hermaphroditismus  femininus  the  suprarenal  cortex  is  usually  found  so 
hyperplastic. 

II.  AGENITALISM   OR  HYPOGENITALISM 

I.  The  Eunuchs 

Occurrence. — The  manifestations  of  agenitalism  or  h}'pogenitalism 
occur  in  the  form  of  a  pure  phj^siological  experiment  in  eunuchs  and  in 
skopzen.  Castration,  as  is  known,  was  very  much  practised  in  antiquity; 
even  until  a  short  time  ago  it  was  carried  out  in  Italy  for  "musical  purposes," 
and  in  the  Orient  it  is  to-day  carried  out  on  the  watchers  of  the  harem, 
and  in  Russia  on  the  religious  sect,  the  skopzen,  on  rehgious  grounds.  All 
these  forms  affect  male  individuals.  As  to  castration  of  females  there 
exists  only  a  very  inexact  report  from  India  by  Roberts. 

S3miptoniatology. — An  excellent  exposition  of  the  symptomatology  has 
been  given  bv  Tandler  and  Grosz,  which  I  shall  in  great  part  follow.     The 


392  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

action  of  castration  is  different  according  to  whether  it  has  been  done  in 
early  youth  or  after  the  entrance  of  puberty. 

We  shall  first  pay  attention  to  the  manifestations  of  loss  of  sexual  glands 
in  males.  When  the  castration  occurred  in  earhest  youth,  the  development 
of  the  accessory  genital  apparatus  is  extremely  deficient.  Penis,  prostate, 
and  seminal  vesicles  remain  small  (Pelikan).  When  castration  has  taken 
place  in  later  years  the  penis  becomes  only  shghtly  smaller,  while  the  pros- 
tate shrinks  to  a  greater  extent.  As  is  known,  castration  has  been  done 
for  prostatic  hypertrophy;  I  shall  consider  in  detail  later  the  action  of  late 
castration. 

In  early  castration  all  sexual  instinct  is  absent,  and  the  small  penis  that 
remains  never  becomes  erect.  As  the  castration  is  not  always  complete. 
it  may  happen  some  of  the  eunuchs  may  still  experience  a  slight  degree  of 
libido,  on  account  of  which  some  of  the  harem-watchers  in  the  Orient  had 
their  penis  removed  wath  the  testicles.  A.  Marie  reports  the  case  of  a  forty- 
year-old  Eg\'ptian  eunuch  who  had  been  castrated  in  childhood,  but  who 
showed  illusory  ideas  that  had  an  erotic  content. 

If  castration  has  been  carried  out  after  development  of  puberty  the 
sexual  instinct — Mobius  calls  it  the  cerebral  sexual  instinct — is  retained 
for  a  long  time;  copulation  is  still  possible  and  there  occurs  an  ejaculation 
of  prostatic  secretion. 

According  to  Gall,  the  cerebellum  should  atrophy,  and  indeed  in  uni- 
lateral castrates  the  opposite  half  of  the  cerebellum.  This  statement  has 
been  contradicted,  although  Mobius  pointed  out  that  no  certain  contradictory 
evidence  has  been  advanced.  According  to  a  personal  communication  of 
Frof.  Tandler.  however,  the  statement  of  Gall  is  certainly  not  in  accordance 
with  fact. 

The  statement  as  to  the  characters  of  castrated  individuals  varies  very 
much.  For  the  most  part  it  is  stated  that  castrates  lack  the  courage,  the 
passions,  and  the  aspiration  of  a  normal  man;  they  are  described  as  tricky, 
revengeful,  and  cruel.  On  the  contrary  the  intellectual  capabilities  are 
not  diminished,  as  many  eunuchs  have  attained  to  influential  positions. 
It  is  hard  to  judge  these  statements,  as  in  the  most  of  the  famous  eunuchs, 
the  history  lacks  exact  knowledge  as  to  the  time  and  the  completeness  of 
the  castration.  Mobius  points  out  that  castrates  lack  the  higher  artistic 
endowTnents.  for  the  Airtuosity  of  castrated  singers  cannot  be  regarded  as 
such.  At  any  rate,  animal  experimentation  shows  that  castrated  animals 
(oxen,  geldings,  capons)  lack  the  courage,  the  animation,  and  passions  of 
normal  male  animals. 

Noteworthy  is  the  influence  of  castration  on  the  skeletal  formation  and 
the  development  of  the  secondary  sexual  characters.  Castration  in  early 
years  leads  in  man  and  animals  to  increase  in  length  (Godard.  Pelikan, 
Pittard,  Becker,  Lortet,  Pirsche,  Sellheim,   Tandler  and  Grosz,   and    others). 


EuxucHS  393 

Eunuchs  of  200  cm.  in  height  are  observed  often.  The  tallness  j&rst  sets  in  at 
the  time  of  puberty.  The  closure  of  the  epiphyses  is  delayed.  Many 
epiphysial  junctures  may  remain  open  until  a  high  age.  The  ossification  of 
the  cranial  sutures  is  also  delayed.  Signs  of  the  frontal,  cranial,  sagittal,  and 
lumboid  sutures  are  retained  for  a  long  time.  Therewith  the  skeleton  shows 
especial  characteristics;  the  head  is  small,  the  tabular  part  of  the  occipital 
bone  is.  according  to  Gall,  flattened.  The  spinal  column  is  especially  short, 
the  extremities  are  lengthened,  especially  in  their  distal  parts,  thus  causing  a 
certain  preponderance  of  the  lower  length  over  the  upper  length  and  a  rela- 
tively large  span  width.  Often  there  is  genu  valgum.  The  breadth  of  the 
shoulders  is  diminished,  the  pelvis  shows  a  mid-form  between  masculine  and 
feminine  type,  and  remains  infantile.  In  the  same  cases  the  sella  turcicajs 
remarkably  large.  I  have  already  remarked  I  cannot  infer  from  this  an 
increase  in  function  of  the  h}^ophysis.  In  the  tall  eunuchoids  the  sella 
turcica,  as  we  shall  see  later,  is  not  enlarged,  but  rather  smaller.  The  larynx 
remains  small,  does  not  ossify,  shows  childish  dimensions,  in  which  the 
laminae  thyroidis  encroach  upon  each  other  at  a  wide  angle  and  the  promi- 
nentia laryngea  is  indistinct;  the  voice  does  not  change,  and  the  childish 
soprano  is  retained.  The  bones,  especially  the  long  tubular  bones  remain 
delicate,  and  the  sites  of  the  muscular  insertions  are  only  very  feebly  developed. 
The  tonus  of  the  muscles  is  slight,  the  phenomena  of  movement  should  take 
place  more  slowly.  The  muscles  are  permeated  with  fat.  The  metabolism 
of  the  muscles  must  become  essentially  altered  through  the  castration,  for  on 
castration  the  meat  of  male  animals  takes  on  the  characteristic  odor,  an 
experience  that  is  extensively  made  use  of  by  breeders. 

The  skin  is  strikingly  delicate  and  pale  and  in  older  castrates  shows  the 
fawn-yellow  coloration  and  wrinkling.  It  is  very  poor  in  pigment.  The 
distribution  of  fat  is  very  characteristic,  fully  corresponding  to  that  which  will 
be  described  under  dystrophia  adiposo-genitalis.  Hence  there  are  found 
pads  of  fat  in  the  hypogastric  region,  and  on  the  mons  Veneris,  the  latter  of 
which  is  bounded  above  by  a  horizontal  fold;  also  on  the  nates,  on  the  hips 
and  thighs,  on  the  mammary  glands  and  laterally  on  the  upper  eyelids  which 
may  hang  down  like  bags.  In  many  cases  there  occurs  pronounced  adiposity. 
Tandler  and  Grosz  distinguish  between  a  tall  and  a  fat  eunuch  t}^e,  al- 
though in  the  first  the  characteristic  distribution  of  fat  is  always  indicated. 
The  muscle  meat  is,  as  in  the  castrated  animals,  permeated  with  fat.  The 
tonus  of  the  musculature  is  slight. 

Finally  the  secondary  sexual  characters  are  deficient.  While  the  hair  of 
the  head  is  dense,  such  individuals  are  beardless,  and  show  only  lanugo  hairs 
on  the  face,  especially  on  the  chin  and  the  upper  lip;  in  later  Hfe,  individual 
bristly  hairs  may  develop,  similar  to  those  that  grow  in  old  women,  on  the 
lateral  parts  of  the  upper  lips.  The  trunk  remains  completel}^  hairless  and 
the  axillary  hairs  are  absent  or  are  sparse.     The  pubic  hairs  are  absent,  or 


394  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

consist  in  only  a  few  sparse  hairs  at  the  root  of  the  penis.     Also  the  peri- 
neum remains  hairless.     The  involution  of  the  thymus  gland  is  slight. 

We  know  much  less  concerning  the  results  of  castration  in  the  youthful 
female  organism.  According  to  the  inexact  statements  of  Roberts  the 
female  castrates  grow  to  be  tall,  the  accessory  apparatus  of  the  genitalia 
remain  entirely  undeveloped,  the  secondary  sexual  characters  and  the  breasts 
do  not  develop.  With  this  rather  agree  the  animal  experiments  of  Hegar, 
Kehrer,  and  others,  and  the  observation  on  female  eunuchoids  that  will  be 
mentioned  later. 

2.  Late  Castrates 

Castration  in  man  after  the  onset  of  puberty  is  carried  out  but  very  rarely. 
In  the  most  cases  the  indication  for  it  is  found  in  tuberculosis  of  the  testicles. 
Later,  in  late  eunuchoidism,  we  will  learn  about  the  group  that  depends  on  a 
traumatic  foundation.  As,  however,  in  most  of  these  cases  the  sexual  glands 
remain  behind  in  the  body  and  are  only  shrunken.  I  classify  these  cases 
with  later  eunuchoidism,  as  it  seems  to  me  of  like  significance  whether  the 
shrinking  of  the  testicle  is  the  result  of  a  traumatic  action  or  of  another 
disease  process. 

If  castration  in  man  takes  place  at  a  relatively  early  age  there  occurs  a 
pronounced  regressive  alteration  of  the  genital  apparatus,  and  at  least 
a  partial  retrogression  of  certain  secondary  sexual  characters,  and  finally  a 
distribution  of  fat  that  is  similar  to  that  of  eunuchs.  It  is  remarkable  that 
I  was  unable  to  find  in  the  literature  an  exact  description  of  such  a  late  eu- 
nuch. From  the  older  literature  I  quote  that  of  Martin:  In  war,  a  piece  of 
shell  tore  away  the  penis  and  testicles  of  a  married  man.  Soon  afterward 
the  man  lost  his  beard  and  his  breasts  began  to  increase  in  circumference. 
More  frequently  is  found  the  statement  that  on  castration  in  already  fully 
developed  individuals  a  retrogression  of  an  already  developed  accessory 
genital  apparatus  and  of  the  secondary  sexual  characters  does  not  occur. 

A  short  time  ago  I  was  able  to  observe  carefully  a  suitable  case,  and  I 
herewith  report  it: 

Observation  XLVII. — Kr.  J.,  forty-nine  years  old.  Entered  the  clinic  July,  1912. 
In  the  eighteenth  year  of  life  he  had  gonorrhea  and  bilateral  orchitis.  In  the  nine- 
teenth year  of  life  he  acquired  lues.  In  the  twenty-first  year  of  life  there  began  a  swell- 
ing of  the  cervical  lymphatic  glands  and  at  the  same  time  a  caries  of  the  lower  jaw;  the 
latter  continuing  three  years  and  disappearing  after  operative  procedure.  In  the  twenty- 
sixth  year  of  life,  both  testicles  were  removed  on  account  of  tuberculosis.  A  year  after 
the  operation  the  patient  suffered  with  cardiac  palpitations,  that  later  disappeared.  In 
the  thirty-seventh  year  of  life  he  developed  a  goiter  after  a  trip  to  the  Stciermark,  which 
goiter  later  receded.     For  several  years  he  has  had  attacks  of  typical  bronchial  asthma. 

Since  the  castration  the  patient  has  gradually  gained  about  30  kg.  The  potentia 
coeundi  still  exists,  but  coitus  is  carried  out  but  very  rarely;  ejaculation  takes  place, 
but  since  the  operation  libido  has  been  very  slight. 


LATE  CASTRATES 


395 


The  mustache,  which  even  before  was  not  developed  very  strongly,  has  become  very 
much  more  sparse  since  the  operation,  so  that  there  exists  on  the  upper  lip  only  a  small 
strip  of  sparse  hairs,  as  is  seen  in  the  accompanying  photograph.  The  beard  on  the  cheek 
is  now  so  sparse  that  the  patient  has  to  shave  himself  much  less  frequently  than  formerly. 
The  hairiness  of  the  mons  \^eneris  is  very  sparse,  it  is  a  Uttle  denser  at  the  root  of  the  penis. 
Here  it  terminates  above  in  a  horizontal  hue. 

The  penis  is  only  3  cm.  long,  the  foreskin  has  become  too  long  and,  therefore,  shows 
numerous  transverse  wrinklings.     In  an  erect  condition  the  penis  is  only  43^  cm.  long. 

The  hairiness  in  the  axillce,  on  the  trunk  and  on 
the  perineum  and  on  the  extremities  is  entirely 
absent. 

The  patient  is  rather  fat,  the  breasts  are  pro- 
nouncedly rich  in  fat,  and  the  hypogastric  region  and 
the  mons  Veneris  are  also  rather  fat. 

The  case  reported  is  not  entirely  free  of 
objections,  as  it  might  be  supposed  that  the 
previous  gonorrhea  and  luetic  infection  and 
the  tuberculosis  may  have  damaged  the 
sexual  glands  seriously  even  before  the  castra- 


FiG.  66. — Late  castrate. 


Fig.  67. — -Genitalia  of  a  late  castrate. 


tion.     Nevertheless  the  statements  of  the  patient  that  the  alterations  de- 
scribed took  place  only  after  the  operation  are  very  precise. 

In  the  female  sex  castration  after  puberty  has  been  carried  out  fre- 
quently by  the  gynecologists.  It  leads  regularly  to  atrophy  of  the  uterus  and 
vagina.  Menstruation  remains  absent.  The  external  genitaha,  especially  the 
chtoris,  shrink,  the  vagina  becomes  narrower.  In  female  animals  the  sexual 
instinct  ceases.  Biicura  experimented  on  rabbits.  If  after  the  castration 
the  female  did  not  admit  the  male,  this  was  a  sure  sign  that  the  operation 
had  succeeded.  Also  after  castration  in  women  is  the  sexual  sense  reduced. 
Gloevecke  found  this  in  78  per  cent.,  PJister  in  js  per  cent.,  AUerthum  in  68 
per  cent.     In  women  who  have  been  having  sexual  intercourse  for  a  long  time, 


396  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

libido  may  be  retained  for  a  while.  In  rare  cases  {Mandl  and  Burger,  Pfister) 
the  libido  may  be  increased  for  a  time  after  the  castration. 

After  the  castration  the  skin  becomes  lighter  on  account  of  loss  of  pig- 
ment (Pfister) .  The  hair  of  the  head  becomes  luxuriant.  There  is  no  distinct 
influence  on  the  shape  of  the  breasts;  but  the  nipples  show  a  slight  grade 
of  atrophy,  and  the  areolae  become  light-rose  in  color  through  partial  loss 
of  pigment. 

As  in  man,  there  is  in  woman  after  castration  a  tendency  to  corpulency. 
Considerable  increase  in  weight  was  found  by  Alterthujn  in  29.5  per  cent., 
hy  Glaevecke  in  57.5  per  cent. 

The  behavior  of  the  respiratory  metabolism  after  castration  has  become 
a  subject  of  lively  discussion.  Lowy  and  Richter  found  in  female  castrated 
animals  the  fundamental  exchange  lowered  about  20  per  cent.,  in  the  males 
about  14  per  cent.  On  administration  of  ovarian  substances  it  again  rose 
to  normal.  Again,  Luthje  has  pointed  out  that  the  slight  reduction  of  the 
fundamental  exchange  was  to  be  referred  to  the  greater  phlegma  of  the 
animal,  v.  Noorden  has  subjected  the  experiments  that  exist  in  the  literature 
to  a  thorough  criticism,  and  comes  to  the  conclusion  that  a  reduction  of  the 
fundamental  exchange  has  not  as  yet  been  strictly  demonstrated.  The 
clinical  observation  of  an  increased  deposit  of  fat  after  castration  is  ever 
known  ''on  account  of  the  broad  basis  on  which  it  rests,  unquestionable." 
Recently,  further  investigations  by  L.  Zuntz  have  been  made  on  three  women 
who  were  castrated  on  account  of  gynecological  complaints.  During  the 
first  week  Zuntz  found  no  distinct  reduction  of  the  fundamental  exchange. 
In  all  cases  there  was  found,  after  a  long  time,  a  slight  fall  of  the  oxygen  con- 
sumption, as  much  as  20  per  cent.  The  administration  of  oophorin  was  not 
able  to  produce  a  distinct  addition  to  the  oxygen  consumption.  We  shall 
see  later  that  also  in  eunuchoidism,  in  the  few  investigations  that  have  been 
made  up  to  the  present,  the  respiratory  metabolism  was  found  to  be  rather 
normal.  There  is  no  ground,  however,  for  the  fact  that  the  corpulency  that 
develops  after  castration  in  a  great  majority  of  cases  docs  not  depend  directly 
on  the  loss  of  the  sexual  gland,  as  small  turnings  of  the  scale  not  demonstrable 
by  our  present  methods  may  amount  to  something  in  the  course  of  years;  and 
as  the  disturbance  in  the  regulation  of  the  fat  metabolism  does  not  depend 
exclusively  on  the  fundamental  exchange  (see  Chapter  XIV). 

Very  little  is  known  as  to  the  other  alterations  of  the  metaboHsm  that 
occur  after  castration.  Also  the  action  of  the  sexual  glandular  substances 
introduced  in  the  organism  has  not  been  sufficiently  studied  up  to  the  present. 
As  we  have  seen  before,  its  influence  on  the  respiratory  metabolism  is  still 
subject  to  controversy.  Many  authors  {Matthis,  Neumann  and  Vas,  and 
others)  found  under  the  influence  of  oophorin  a  slight  increase  in  the  elimina- 
tion of  nitrogen,  and  an  increase  of  the  elimination  of  salts,  especially  of 
the  elimination  of  phosphorus  through  the  intestine. 


EUNUCHOIDISM  397 

Cristofoletti  saw  after  the  administration  of  ovarian  substances  the  glyco- 
suric  action  of  adrenahn  become  weaker. 

In  woman,  the  acute  loss  of  the  sexual  glands  leads,  as  is  known,  to  a  series 
of  manifold  excitatory  states  of  the  vegetative  nervous  system.  Drawing 
pains,  emotional  excitements,  feeling  of  anxiety,  headache,  fainting  spells, 
heat  and  feeling  of  cold,  disturbance  of  the  intestinal  tract,  weakness  of 
memory,  and  mental  depression  occur.  The  wave-movement  ceases.  The 
manifestations  become  intelligible  when  we  consider  what  distinct  revolutions 
occur  in  the  female  organism  after  castration. 

Cristofoletti  saw  after  castration  (also  in  animal  experiments)  increase  of 
the  glycosuric  action  of  adrenalin.  Alder  found  delay  in  the  coagulation- 
time  of  the  blood  and  reduction  of  the  calcium  in  the  blood. 

As  is  known,  all  these  manifestations  occur  also  at  the  climacteric. 
*' Castration  produces  an  artificial  climax,  that  is  like  the  natural  one,  and 
often  transcends  it  in  pathological  manifestations"  {W.  H.  Freund). 

The  treatment  of  eunuchoidism  will  be  considered  further  on. 

3.  Eunuchoidism 

Dystrophia  adiposo-genitalis,  gerodermia  genito-distrofico,  obesite 
d'origine  genitale. 

Definition. — Eunuchoids  we  term,  according  to  Tandler  and  Grosz,  indi- 
viduals who,  without  being  castrated,  entirely  simulate  in  their  clinical  mani- 
festations the  true  eunuch  type,  or  at  least  are  extraordinarily  similar  to  it. 
They  are  either  tall,  or  if  complications  are  absent,  are  at  least  not  stunted  in 
growth;  they  show  the  typical  fat  distribution  of  eunuchs,  and  eventually  pro- 
nounced obesity;  the  epiphysial  junctures  persist  abnormally  long,  the  skeletal 
dimensions  are  characterized  by  an  especial  length  of  the  extremities,  and  fur- 
thermore the  individuals  show  a  definite  psychical  habitus.  Finally  there  is 
found  a  more  or  less  pronounced  disturbance  of  development  of  the  genitalia 
with  faulty  development  of  the  secondary  sexual  characters.  It  is  probable  that 
in  such  cases  we  have  to  do  with  a  developmental  disturbance  beginning  primarily 
in  the  sexual  glands,  and  indeed  especially  the  interstitial  glands,  as  functional 
disturbances  of  the  generative  glands  alone  do  not  lead  to  eunuchoidism. 

Historical  and  Case  Histories. — Such  a  case  was  first  termed  eunuchoid 
by  Griffith.  A  sharp  delimitation  of  the  clinical  picture  occurred  only  a 
short  time  ago,  when  Tandler  and  Grosz  first  reported  a  series  of  cases  and 
then  described  the  clinical  picture  thoroughly.  Even  before  Tandler  and 
Grosz,  however,  a  great  number  of  such  cases  had  been  reported  in  the  litera- 
ture under  very  different  names. 

Meige  mentions  a  case  of  Reichlin's  that  was  a  pronounced  eunuchoid. 
Moreover  Tandler  and  Grosz  regard  as  an  eunuchoid  the  case  of  Redlich. 
Similar  cases  were  described  by  Kisch.     Kisch  distinguishes  between  heredi- 


398  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

tary  and  acquired  obesity  and  divides  the  hereditary  obesity  into  two  forms, 
one  of  which  develops  in  early  youth  and  which  becomes  prominent  later,  and 
in  which  only  the  predisposition  to  obesity  is  inherited.  Then  Kisch  men- 
tioned that  the  hereditary  obesity  '*  acquires  a  quite  characteristic  nutritive 
expression  of  degeneration.''  The  description  of  these  types  that  Kisch 
furnishes  suits  entirely,  as  Tandlera.ndGrosz  ^ointi  out,  the  eunuchoid  type. 
Among  two  hundred  thirty-eight  cases  of  obesity,  Kisch  saw  it  twenty-four 
times,  seventeen  of  these  cases  developing  at  an  early  age. 

Pirsche  cites  the  case  of  Papillaunet  and  adds  three  observations  of  his 
own.  Other  cases  have  been  reported  by  Etienne.  Jeandelize  and  Richon 
(man  fifty-nine  years  old,  174  cm.  tall,  preponderance  of  the  lower  length, 
epiphysial  junctures  incompletely  closed,  the  testicles — one  cryptorchichtic — • 
very  small  and  fibrous,  seminal  vesicles  and  prostate  also  small  and  fibrous, 
penis  4  cm.  long);  and  by  Duckworth  (thirty-seven-year-old  man,  171. 7  cm. 
tall,  179  cm.  span  width,  considerable  preponderance  of  the  lower  length, 
marked  fibrosis  of  the  testicles,  the  prostate,  and  the  epididymis,  already 
described  by  Griffith) ;  already  Duckworth  mentions  the  similarity  to  "cryptor- 
chid  conformation."  Very  worthy  of  mention  are  the  cases  of  Sainton  of  five 
brothers  (and  sisters),  three  were  eunuchoids,  and  besides  this  an  uncle  and 
great-uncle.  The  case  described  was  172  cm.  tall.  The  lower  length 
predominated  considerably.  The  thymus  gland  was  not  persistent.  I 
believe  that  also  the  case  of  Bahonneix  and  Paisseau  (case  I)  and  that  of 
Lemos  Magalhaes  belong  to  this  group;  also  the  case  of  Thihierge  and  Gastinel 
(termed  gigantism  with  infantihsm). 

Xeurath  furnishes  the  description  of  an  eleven-year-old  tall-grown  girl 
with  typical  "eunuchoid"  obesity,  that  is  very  likely  a  case  of  eunuchoidism. 

Also  the  case  of  Porhon  and  Mihaelesco  described  by  these  authors  as 
"cas  d'infantilesme  dysthyreoidique  et  dysorchitique''  seems  to  me  to 
belong  to  this  group,  as  also  the  case  of  "anorchidia"  of  Launois  and  Roy. 

Also  the  case  of  " cryporchides  abdominaux"  Variot;  also  a  case  of  Apert, 
also  case  I  of  Bahonneix  and  Paisseau  would  fit  in  this  group  very  well. 

Of  special  interest  is  the  case  of  Josefson  and  Lundquist  that  aft"ected  a 
female  eunuchoid,  I  shall  consider  this  in  detail  later  on.  I  also  mention  here 
briefly  the  case  of  Peritz. 

During  the  course  of  the  last  few  years,  I  have  seen  four  cases,  which  I 
shall  report,  before  entering  into  the  description  of  the  sym.ptomatology. 

Observation  XLVIII. — B.  Sch.,  thirteen  and  one-half  years.  First  observed  Nov., 
1910.  Father  had  lues  at  the  age  of  twenty  years.  His  Wassermann  still  positive.  Asa 
child  the  patient  had  an  umbilical  hernia,  and  a  left-sided  inguinal  hernia,  also  slight  con- 
stipation. The  umbilical  hernia  healed  three  months  after  birth,  the  inguinal  hernia 
only  after  some  j-ears,  three  years  ago  operation  on  the  tonsils. 

Before  this,  always  sore  throat  and  snorings.  For  about  three  j-ears  gradual  onset  of 
obesity.  In  addition  vomiting  sometimes,  especially  after  breakfast.  When  the  vomit- 
ing has  finished,  appetite  returns.     The  boy  now  weighs  5532  kg.     The  body  build  is 


EUNUCHOIDISM 


399 


slender.  The  skin  pale,  soft,  satiny,  facial  complexion  pale,  marked  collection  of  fat 
on  the  breasts,  in  the  inguinal  region  and  on  the  mons  Veneris.  The  penis  is  quite  small, 
as  is  also  the  scrotum;  the  right  testicle  is  about  the  size  of  a  plum-kernel,  the  left  is  about 
half  the  size  and  is  not  quite  descended.  Examination  of  the  eyes  shows  entirely  normal 
relations.  Likewise  the  X-ray  examination  of  the  skull  [i.e.,  normal].  Sella  turcica 
rather  small.     Temperature  36.2°,  circumference  of  the  head  54  cm. 

Erythrocytes,  5,290,000 

Hemoglobin,  95  per  cent. 

Leucocytes,  10,700,  of  which: 

Polymorphonuclear  neutrophils,  49.6  per  cent. 

Large  mononuclears,  3  per  cent. 

Lymphocytes,  42.4  per  cent. 

Eosinophiles,  5  per  cent. 

Genu  valgum  on  each  side. 

The  boy  is  well  developed  mentally,  but  lazy. 
He  is  silent,  especially  in  intercourse  with  com- 
panions of  the  same  age. 

Thyroid  small,  hardly  palpable.  Liver  and 
spleen  not  enlarged. 

Thyroid  gland  treatment.     Loss  of  about  3  kg. 

June,  191 1.  The  boy  has  grown,  still  very  fat, 
typical  distribution  of  fat.  The  testicles  are  not 
better  developed.  The  right  testicle  has  a  longi- 
tudinal diameter  of  about  25  mm.,  the  left  of  about 
18  mm.,  the  latter  is  fully  descended. 

Leucocytes,  10,800,  of  which: 

Polymorphonuclear  neutrophiles,  50.94  per  cent. 

Lymphocytes,  31.26  per  cent. 

Large  mononuclears,  12.8  per  cent. 

EosinophUes,  3  per  cent. 

Eye  examination  normal. 

Jan.,  191 2.  A  new  X-ray  examination  of  the 
skull  showed  that  size  of  the  sella  turcica  had  not 
essentially  altered.  The  examination  by  a  perime- 
ter,_  showed  an  entirely  normal  visual  field.  The 
thyroid  treatment  was  tried  once  more,  which, 
however,  soon  led  to  slight  signs  of  hyperthyroid- 
ism and  hence  had  to  be  abandoned.  The  patient 
was  then  ordered  radium  baths  three  times  a  week 
with  100,000  Mache  units  per  bath,  which  per- 
haps exercised  a  favorable  influence.  At  all  events 
there  became  apparent  a  distinct  progress  of  the 
development,  as  even  the  patient  thought  in  June, 
1912.  The  patient  was  now  174  cm.  tall  and  still 
somewhat  fat.     Abundant  fat  deposits  were  to  be 

found  in  the  hypogastric  region.  The  pubic  hairs  were  now  well  grown,  but  still  showed 
a  horizontal  boundary  above.  The  trunk  was  still  fully  bald,  and  only  in  the  axilla  on 
both  sides  were  a  few  sparse  hairs  to  be  seen.  The  size  of  the  penis  and  the  testicles 
corresponded  to  the  age  of  the  patient.  It  was  stated  that  pollutions  had  not  as  yet 
occurred.  The  voice  had  changed  and  the  patient  complained  only  very  rareh^  of 
headaches.     Some  adenoid  vegetations  in  the  nose  were  now  removed. 


Fig.  68. — Case  of  eunuchoidism 
(Observation  XL VIII). 


400 


THE    DISEASES    OF    THE    SEXUAL    GLANDS 


Fig.  69. — Sella  turcica  in  eunuchoidism  (Observation  XL VIII). 


EUNUCHOIDISM 


401 


Summary. — Here  was  a  typical  case  of  eunuchoidism.  The  headaches  and  the  occa- 
sional vomitings  at  first  awakened  the  thought  of  a  hypophysial  tumor;  but  the  X-ray 
examination  of  the  skull  and  the  observations,  continued  for  three  years,  and  especially 
the  absence  of  an  inhibition  of  growth,  ruled  out  this  possibility,  the  inhibition  of  develop- 
ment seemed  to  be  only  transitory,  that  has  re- 
cently been  made  up  for  very  considerably. 

Observation  XLIX. — Dat.,  from  Jerusalem, 
twenty  years  old.  Entered  the  clinic  Dec,  1905. 
Typhoid  fever  at  the  age  of  sixteen  years;  since 
this  time  chronic  enteritis.  Total  length  159  cm., 
circumference  of  head  57  cm.,  of  breast  74  cm., 
of  abdomen  87  cm.,  anterior  superior  spine  to  in- 
ternal malleolus  88  cm.,  acromion  to  styloid 
process  of  radius  57  cm.,  acromion  to  oleocranon 
35  cm. 

Distantia  spin,  26  cm. 

Distantia  crist,  273^^  cm. 

Distantia  trochant,  29  cm. 

Slender  build,  marked  emaciation,  except  that 
there  are  fat  deposits  on  the  hips  and  mons 
Veneris.  MUk-teeth  in  part  retained.  The 
penis  and  scrotum  quite  small.  Testicles  on 
both  sides  in  the  inguinal  canal;  very  few  hairs 
at  the  root  of  the  penis.  No  hairs  in  the  axillae, 
no  beard.     Never  erections,  no  libido. 

Marked  hyperextensibility  of  the  joints,  espe- 
cially the  phalangeal  joints  of  the  fingers.  The 
fingers  can  be  bent  backward  to  a  right  angle, 
and  the  knees  can  rest  comfortably  in  the  axillae. 
Fingers  are  very  long  and  slender. 

Sexual  life  entirely  absent. 

X-ray  examination  shows  that  the  distal  epi- 
physial junctures  of  the  ulna  and  radius,  the 
proximal  of  the  first  metacarpal  bones  and  proxi- 
mal of  the  phalanges  are  still  open;  the  bones 
seem  rarefied. 

The  sella  turcica  is  rather  small. 

Striking  is  a  short,  round,  and  sharply  de- 
lineated calcification  in  the  anterior  part  of  the 
sella  turcica  immediately  beneath  the  clinoid 
process. 

Slight  genua  valga. 

Voice  high. 

Indistinct  prominentia  laryngea. 

Thyroid  not  palpable. 

Test  for  alimentary  glycosuria  (100  and  150 
gm.  dextrose  respectively)  negative. 

Observation  L. — M.  W.,  twenty-three  years 
old.     March,    1903.     Genitalia    hypoplastic,    as 

far  back  as  patient  can  remember.     Deposits  of   fat  on  the  mons   \'eneris  and   hips, 
which  during  the  last  few  years  have  become  more  strongly  developed.     Never  libido 
26 


\ 


K 


Fig.  70. — Case  of  eunuchoidism 
(Observation  XLIX). 


402 


THE    DISEASES    OF    THE    SEXUAL    GLANDS 


erections  often  since  the  eighteenth  year,  during  which  the  penis  becomes  about  3  cm.  long. 
Has  never  had  sexual  intercourse.  Recently,  several  pollutions.  Patient  is  i6g  cm.  tall. 
Length  of  lower  extremities  (from  ant.  sup.  spine  of  ileum  to  int.  malleolus)  87  cm.; 
length  of  the  upper  extremities  (from  head  of  humerus  to  end  of  third  finger)  76  cm. 
Span  width  184  cm.,  genu  valga.  Copious  deposits  of  fat  on  the  hips,  on  the  outer  sides 
of  the  thigh  and  on  mons  ^'eneris.  INIammae  not  very  rich  in  fat.  No  beard  hairs  at  all. 
Abundance  of  hair  on  head.  Hairs  in  axillae  sparse;  pubic  hairs  present,  not  very  luxuri- 
ant, bounded  above  by  a  horizontal  line.  Xo  hairs  on  the  linea  alba.  Xo  hairs  on  the 
thighs.  Genitalia  hj^ioplastic.  Penis  small,  scarcely  i}i  cm.  long.  Each  testicle 
about  size  of  a  bean.  soft. 


Fig.  71. — Eunuchoidism  (Obser- 
vation L). 


Fig. 


-Genitalia  in  case  ^l.  W.  (Observation  L). 


X-ray. — Sella  turcica  normal,  the  distal  epiphysial  junctures  of  the  radius  and  ulna, 
and  the  proximal  of  the  first  metacarpal  phalanges  are  still  open. 

Leucocytes,  7600  of  which  46  per  cent,  are  neutrophilic  polymorphonuclear  cells. 
Voice  higher.  Prominentia  larjmgea  not  palpable.  Thyroid  gland  not  distinctly  palpa- 
ble. Test  for  alimentary  glycosuria  (100  and  150  gm.  dextrose)  negative.  Character: 
Silent,  not  communicative,  somewhat  sh3^     Intelligence  normal. 

Observation  LI. — H.  Ad.,  twenty-eight  j'^ears.  Entered  clinic  April,  191 2.  The  patient 
had  nine  brothers  and  sisters,  five  of  whom  died  shortly  after  birth.  One  sister  had  chloro- 
sis. One  brother  when  a  child  apparently  had  laryngospasm.  Since  his  sixteenth  year 
the  patient  has  suffered  with  a  gradually  increasing  chronic  exudative  articular  rheuma- 
tism. He  states  that  once  during  an  exacerbation  of  the  joint  afi'ection,  he  lost  much 
weight.     Then  in  the  twenty-first  year  he  was  at  a  bath-resort  and  in  a  short  time, 


EUNUCHOIDISM 


403 


Fig.  73. — Sella  in  a  case  of  eunuchoidism  (Observation  L). 


404 


THE    DISEASES    OF    THE    SEXUAL    GLANDS 


gained  42  to  48  kg.  Later  this  became  obesity. 
Then  during  another  attack  of  articular  rheumatism 
he  again  lost  weight.  Now  the  body  weight  is 
661 2  kg. 

The  patient  states  that  he  has  experienced  sexual 
sensations  since  the  twelfth  year  of  life.  Later  he 
often  had  erections,  in  which  the  penis  became  quite 
stiff.  His  inclination  was  always  for  young  boys, 
however,  and  occasionally  he  practised  active  pe- 
derasty. Since  his  sixteenth  year,  his  inclination 
gradually  turned  to  women,  but  the  libido  was  never 
very  strong.  He  had  love-episodes  but  he  never 
attempted  coitus,  as  he  knew  that  he  was  im- 
potent. Later,  never  pollutions;  the  penis  has 
always  been  very  small. 

The  patient  is  176  cm.  tall,  of  typical  eunuch- 
oidal  form  and  dimensions.  The  span  width  is 
185I2  cm.,  the  lower  length  nearly  100  cm.  The 
thorax  is  small  in  relation  to  the  pelvis,  the  head  is 
small,  the  prominentia  laryngea  is  only  indicated. 
Bilateral  genua  valga. 

The  patient  is  very  intelligent  but  very  taciturn 
speaking  only  when  he  is  spoken  to.  The  [mental] 
attitude  is  often  depressed. 

The  voice  is  high,  the  thyroid  gland  not  distinctly 
palpable.  Typical  distribution  of  fat,  and  a  thick 
pad  of  fat  on  and  superior  to  the  mons  Veneris. 
ALarked  fat  collection  in  the  hypogastric  region, 
which  is  separated  from  the  mons  Veneris  by  a  deep 
fissure,  also  fat  on  the  outer  sides  of  the  thighs  and 
on  the  buttocks.  The  breasts  are  very  rich  in  fat. 
On  the  hips  are  strise  (the  results  of  former  obesity). 
Hair. — No  beard,  no  axillary  hairs,  hairs  on  the 
mons  Veneris  only  sparse,  forming  a  horizontal  line 
above.  No  perineal  hair.  Hair  on  the  trunk  other- 
wise absent. 

The  penis  is  3  cm.  long,  as  in  a  five-year-old 
boy.  The  testicles  are  palpable  in  the  scrotum, 
above  the  size  of  beans,  very  soft.  The  prostate  is 
very    small. 

The  breadth  of  the  heart   as  shown  by  X-ray 
examination  is  only  loj-^  cm. 
•  The  X-ray  examination  of  the  skull  shows  a 
small  but  otherwise  well  formed  sella  turcica.     X-ray  examination  of  the  hand  shows  that 
the  proximal  epiphysial  junctures  of  the  phalanges  are  still  open,  and  that  the  distal  are 
closed.     Open  are  the  proximal  of  the  first  metacarpal  and  the  distal  of  the  radius  and  ulna. 
Blood  examination:  Erythrocytes,  5,800,000. 
Hemoglobin,  75  per  cent. 
Leucocytes,  5500,  of  which: 
Neutrophils,  59  per  cent. 
Lymphocytes,    163^2  Pt^r  cent. 
Large  mononuclears,    22)2  per  cent. 
Eosinophiles,  3  per  cent. 


Fig.   74- 


-Eunuchoidism  (Obscr\-a- 
tionLI). 


EUNUCHOIDISM 

Examination  of  the  respiratory  metabolism  {Dr.  Bernstein). 

CO2  in  cc.  O2  in  cc. 

176.5  221.0 


405 


CO2 

2.67 


O2 
3-31 


RQ 

0.8088 


According  to  this  the  oxygen  consumption  is  entirely  normal. 
Test  as  to  alimentary  glycosuria  (100  and  later  200  gm.  dextrose  negative). 
Summary. — Typical  case  of  eunuchoidism,  in  which  a  slight  function  of  the  sexual 
glands  was  present  at  the  time  of  puberty,  which,  however,  soon  disappeared. 

S5miptomatology. — The  form  of  eunuchoids  is  characterized  by  its  slender- 
ness.  Even  in  fat  individuals  the  bony  build  is  slender,  and  especially  the 
tubular  bones  are  striking  by  their  length.  The  head  is  small,  the  hands 
are  slender  and  long.  This  is  well  shown  in  the  accompanying  photographs. 
Tallness  is  the  rule  in  most  of  the  cases.     There  are  cases  known  that  were 


Fig.   75. — Genitalia  in  Case  H  (Observation  LI). 

nearly  200  cm.  tall.  As  far  as  I  can  judge  by  the  literature,  individuals  with 
eunuchoidism  who  are  not  pronouncedly  tall  are  never,  on  the  other  hand, 
small.  In  the  case  I  reported  the  height  is  never  below  what  corresponds  to 
the  age.  Only  case  Da  is  small,  but  here  the  parents  are  very  small.  Hence 
there  usually  exists  abnormal  tallness  and  at  all  events  never,  unless  especial 
complications  should  exist,  stunting  of  growth.  We  shall  see  later  that  this 
is  important  for  differential  diagnosis  from  hypophysial  dystrophy. 

The  dimensions  of  the  skeleton  in  eunuchoidism  are  characterized  by  the 
especial  length  of  the  extremities.  There  is  almost  always  found  an  excess 
of  the  lower  length  over  the  upper  length  and  of  the  span  width  over  the  body 
length.     I  quote  some  examples.     In  the  case  of  Duckworth  the  body  length 


Fig.  76. — X-ra}'  picture  of  the  hand  in  eunuchoidism  (Observation  LI). 


EUNUCHOIDISM  407 

was  1 7 1. 7  cm.,  the  span  width  179  cm.  in  Observation  LI,  H.,  the  length 
was  176  cm.,  the' span  width  1853^^  cm.,  the  lower  length  100  cm.  In 
Observation  L,  the  height  was  169,  the  span  width  184.  The  tallness  and 
the  preponderance  of  the  length  of  the  extremities  is  brought  about  by  an 
abnormally  long  remaining  open  of  certain  epiphysial  junctures,  namely, 
those  which  usually  ossify  the  latest.  According  to  Tandler  and  Grosz  they 
are  chiefly  the  following:  The  sternal  end  of  the  clavicle,  the  proximal  end 
of  the  humerus,  the  distal  ends  of  the  radius  and  ulna,  the  distal  of  the  tibia 
and  fibula,  the  crista  ilei,  the  tuber  ischii.  Often  at  the  site  of  the  coronal 
and  the  parietooccipital  sutures  is  found  a  tertiary  suture  formation. 
The  root  of  the  nose  is  often  deeply  saddled.  On  the  contrary  the  bone- 
nuclei  are  apparently  always  correspondingly  well-developed.  At  least  in 
•Observation  Sch,  I  could  find  at  the  fourteenth  and  at  the  sixteenth  years  of 
his  life  that  there  was  a  development  of  the  bone  nuclei  corresponding  to  his 
age.  Also  in  Observation  W.  M.  (twenty- three  years)  and  in  Da  (twenty 
years)  the  bone  nuclei  are  already  developed  very  well. 

At  later  years  the  junctures  may  be  fully  closed  (Case  Thihierger  and 
Gastinel) . 

The  sella  turcica,  so  far  as  observations  have  been  made  on  it  is  normal 
in  size  or  rather  small  {Tandler  and  Grosz,  also  the  author'' s  observations). 
This  agrees  with  the  observations  of  Eppinger,  that  in  women  with  infantile 
genitalia,  the  sella  turcica  is  rather  small.  In  my  case  a  small  focus  of  calci- 
fication was  found  on  X-ray  examination  (Observation  Da). 

Almost  always  there  are  genua  valga.  These  were  always  present  in  my 
cases.  Moreover,  I  could  often  observe  the  hyperextensibility  of  the  joints, 
especially  of  the  phalanges  of  the  fingers  (confer  case  Da).  At  the  diaphyses 
the  bones  are  commonly  rarefied. 

The  dentition  is  sometimes  retarded.  In  Observation  Da,  milk-teeth 
were  present  at  the  twentieth  year. 

The  lary^nx  remains  cartilaginous  and  retains  the  dimensions  of  child- 
hood. The  angle  of  the  lamiuce  thyroidae  remains  wide.  The  prominentia 
laryngea  is  otily  slight.  In  highly  pronounced  cases  voice  remains  high 
and  is  usually  shrill. 

All  cases  show  the  typical  distribution  of  fat,  that  is,  pads  of  fat  on  the 
mons  Veneris  and  the  hypogastric  region,  which  latter  is  separated  from  the 
mons  Veneris  by  a  deep  furrow.  Moreover,  there  are  copious  fat  deposits 
on  the  buttocks  and  on  the  outer  sides  of  the  thighs,  and  fat  deposits  in  the 
breasts.  Tandler  and  Grosz  distinguish,  as  in  true  eunuchs,  a  tall  and  a  fat 
type.  The  tall  individual  always  shows  the  eunuchoid  distribution  of  fat, 
however.  Also  in  these  individuals,  who  from  some  reason  or  other  have  lost 
weight,  is  the  distribution  of  fat  always  at  least  indicated  by  an  inclination 
to  become  fat.  When  the  conditions  are  favorable,  the  obesity  develops 
surprisingly  rapidly  (confer  Observation  H).      It  may  attain  an  excessive. 


4o8  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

degree.  Tandler  and  Grosz  report  a  case  in  which  a  6  kg.  pad  of  fat  was  re- 
moved by  operation  from  the  hypogastric  region,  which  removal  seemed  to 
make  the  patient  easier. 

The  hair  of  the  head  is  abundant.  There  are  often  lanugo  hairs  on  the 
face,  especially  in  front  of  the  ears  and  on  the  chin  and  upper  lip.  There  are 
no  mustache  and  beard.  In  later  years  occur  on  the  lower  jaw  sparse  bristly 
hairs,  such  as  are  seen  in  old  women.  The  hair  in  the  axillge  is  absent  or 
only  sparse,  that  on  the  mons  Veneris  is  limited  to  a  few  short  hairs  at  the 
root  of  the  penis.  When  they  are  more  abundant  in  this  situation  they  are 
limited  above  by  a  horizontal  line.  There  are  no  hairs  on  the  perineum;  nor 
on  the  trunk  and  extremities. 

The  skin  is  remarkably  dehcate,  pale,  velvety,  and  sometimes  has  a  fawn- 
yellowish  color.     The  face  in  older  individuals  often  shows  folds  and  wrinkles. 

As  a  rule  the  musculature  is  but  Httle  developed,  and  shows  but  sHght 
tonus. 

In  most  cases  the  thyroid  glands  seem  to  have  a  slighter  volume,  at  least 
the  statement  is  repeatedly  made  that  the  thyroid  was  not  palpable. 

The  genitaha  are  pronouncedly  hypoplastic.  The  penis  is  always  very 
small  and  sometimes  quite  buried  in  the  fat  pad  on  the  mons  Veneris.  The 
scrotum  is  small  and  smooth  and  hairless.  The  prostate  is  small.  The 
testicles  are  small,  soft,  and  sometimes  not  larger  than  a  pea.  Sometimes 
they  are  not  or  only  partially  descended  on  one  or  both  sides.  In  this  case 
the  inguinal  canals  are  open.  Autopsies  were  made  in  the  case  of  Etienne, 
Jeandelize  and  Richon,  and  in  the  case  of  Duckworth  and  of  Tandler  and  Grosz. 
In  the  case  first  named  the  testicles  were  very  small,  fibrous  (3  gm.),  the  inter- 
stitial glands  were  degenerated.  Also  the  prostate  was  very  fibrous.  On 
microscopical  examination,  Tandler  and  Grosz  found  sparse  seminal  canals 
and  sparsely  developed  interstitial  substance.  Also  the  seminal  vesicles 
were  small,  but  the  epididymis  on  the  other  hand,  well  developed. 

Cases  of  female  eunuchoidism  seem  to  be  rare.  Josef  son  and  Lundquist 
have  reported  such  a  case,  which  I  shall  quote  somewhat  in  detail. 

Thirty-four-year-old  woman  who  had  kept  on  growing  from  the  fifteenth  year  on 
(the  growth  had  been  especially  active  up  to  the  twenty-fourth  year);  she  was  183.6 
cm.  tall  (upper  length  118  cm.),  she  had  never  menstruated  and  had  felt  only  slight  in- 
clination for  men;  the  mamm£E  were  small,  flat,  without  palpable  glandular  substances, 
the  nipples  very  small;  she  had  rather  a  mannish  appearance,  but  a  feminine  voice.  The 
form  of  the  pelvis  was  rather  womanly.  The  epiphysial  junctures  were  closed,  the  sella 
turcica  not  enlarged.  Examination  of  the  genitalia  showed  very  small  labia  minora,  a 
hypertrophic  clitoris,  the  vestibule  was  rather  narrow,  the  internal  genitalia  were  not 
palpable.     No  introitus  vagina?  or  hymen. 

In  eunuchoids  the  genital  function  is  always  markedly  reduced  or  entirely 
absent.  In  many  cases,  however,  erections  are  possible  despite  the  smallness 
of  the  penis.     I  refer  to  the  Observations  Da  and  H.     In  many  cases  libido 


EUNUCHOIDISM  409 

is  entirely  absent,  although  it  may  be  present  slightly.  In  one  of  my  cases 
the  inclination  was  at  first  contrasexual.  In  many  cases  potency  can  exist 
for  some  time,  but  this  becomes  less  after  some  years  and  disappears.  In 
other  cases  the  inhibition  of  development  and  disturbance  of  function  occurs 
chiefly  at  the  time  of  puberty  and  later  becomes  compensated  (transitory 
eunuchoidism).  We  may  regard  both  as  formes  frustes.  As  a  case  of  the 
first  form  I  would  regard  case  II  of  Josef  son  and  Lundquist.  It  was  that  of  a 
forty-five-year-old  man  who  had  been  married  since  the  thirty-sixth  year  and 
who  was  entirely  impotent  for  three  years.  The  breasts  had  been  very  rich  in 
fat  ever  since  youth  and  the  pubic  hairs  ended  above  in  a  horizontal  line,  the 
voice  had  not  changed,  the  hairs  of  the  beard  and  in  the  axillae  were  very 
sparse,  trunk  hairless. 

Eunuchoids  of  the  male  and  female  sex  are  always  sterile.  At  least  no 
case  of  procreation  or  conception  is  known. 

In  woman,  the  breasts  are  poorly  developed  or  fatty,  but  poor  in  glandular 
substances;  in  man  they  often  contain  much  fat. 

Observations  on  the  respiratory  metabolism  have  as  yet  been  confined  to 
Observation  H  and  to  a  female  eunuchoid  of  L.  Zuntz's.  The  value  of  O2 
requirements  is  entirely  normal.  Of  course  from  which  we  are  not  justified 
in  concluding  that  in  such  cases  we  may  not  have  had  a  slight  degree  of 
endogenous  obesity,  as  small  differences  may  not  be  evident  on  investigation, 
and  yet  through  summation  may  favor  deposition  of  fat.  It  is  certain  that  in 
all  these  cases  there  is  present  an  abnormal  disposition  for  the  deposition  of 
fat,  as  was  observed  for  example  in  the  case  of  H.  At  all  events  the  cause 
may  be  due  chiefly  to  the  slight  inclination  for  movement  and  to  the  indi- 
vidual's phlegma. 

Test  for  alimentary  glycosuria  was  undertaken  in  three  of  my  cases,  with 
150-200  gm.  dextrose,  and  always  resulted  negative.  Hence  the  assimilation 
limits  for  carbohydrates  seem  to  be  high. 

Guggenheimer  reports  a  case  in  which  at  an  old  age  diabetes  developed.  I 
cannot  see  here  an  especial  connection  with  eunuchoidism.  In  eunuchoidism 
(as  in  normal  individuals)  there  may  very  well  set  in  a  degeneration  of  the 
pancreatic  insular  apparatus.  Another  case  of  eunuchoidism  with  diabetes 
seems  to  be  the  "giant"  described  by  Uhthof.  This  patient  at  the  age  of  six- 
teen years  suffered  an  attack  of  pneumonia.  From  then  an  abnormal  growth. 
He  was  194  cm.  tall,  hands  and  feet  wxre  not  especially  large.  There  existed 
bilateral  cryptorchidism,  the  pubic  hairs  were  sparse,  and  he  had  never  been 
potent. 

The  purin  metabolism  has  been  studied  (not  published)  in  one  case  only. 
Observation  H  of  Nowaczinski  and  myself.  The  endogenous  uric  acid 
elimination  was  normal.  Purin  administered  exogenously  was  well  elimi- 
nated. Perhaps  this  behavior  is  of  differential  diagnostic  importance  as 
against  hypophysial  dystrophy. 


4IO  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

The  blood  examined  in  my  case  showed  normal  values  for  erythrocytes 
and  hemoglobin.  The  leucocyte  count  was  near  normal;  in  all  cases  there 
existed  a  pronounced  mononucleosis.  Lately  also  Guggenheimer  has  found 
the  marked  predominance  of  lymphocytes  in  several  cases  of  eunuchoidism; 
in  one  case  he  saw  hyperleucocytosis  with  predominance  of  the  mononuclear 
cells.  ^ 

The  thymus  gland  showed  abnormally  slight  involution  {Kolisko,  and 
Tandler  and  Gross) . 

The  findings  in  the  internal  organs  show  no  essential  alterations,  except 
such  as  must  be  regarded  as  coincident.  In  one  case  the  heart  shadow  as 
shown  by  the  X-ray  was  seen  by  me  to  be  strikingly  small. 

Perhaps  the  excitability  of  the  vegetative  nerves  in  cases  of  eunuchoid- 
ism is  somewhat  reduced.  This  was  tested  in  some  cases  with  pilocarpine 
and  adrenalin,  yielding  a  slight,  but  distinct,  reaction. 

The  development  of  the  intelligence  in  such  individuals  is  mostly  entirely 
normal.  Feeble-mindedness,  which  has  been  observed  in  some  cases,  is  to 
be  referred  to  other  coincident  developmental  disturbances.  On  the 
contrary,  certain  common  traits  do  exist  in  the  psyche  of  eunuchoids.  They 
are,  as  Tandler  and  Grosz  notice,  strikingly  quiet,  but  little  communicative, 
and  often  but  slightly  independent.  At  any  rate  this  mental  condition  is  not 
tope  designated  as  infantile.     The  masculine  quality  is  all  that  is  lacking. 

Occurrence  and  Pathogenesis. — Eunuchoidism,  at  least  as  far  as  its  pro- 
nounced forms  are  concerned,  occurs  essentially  more  frequently  in  the  male 
sex.  Thus  far  the  only  typical  incontestable  case  in  woman  has  been  reported 
by  Josejson  and  Lundquist.  Perhaps  to  this  may  be  added  the  previously 
quoted  cases  of  Swinarski,  Pfannenstiel,  and  of  Howitz.  But  here  there  are  no 
statements  as  to  the  proportions  of  the  body,  which  would  be  very  important 
for  the  diagnosis.  Animal  experiments  show  us  that  castration  in  early  life 
produces  long-legged  individuals  in  the  female  also.  We  know  very  little  as 
to  the  cause  of  the  developmental  disturbances  in  the  sexual  glands.  As  was 
mentioned  previously,  eunuchoidism  in  the  male  sex  is  very  frequently  asso- 
ciated with  cryptorchidism.  This  may  be  either  abdominal  or  inguinal.  It 
may  w^ell  be  regarded  as  a  partial  manifestation  of  the  developmental  dis- 
turbances and  not  as  its  cause.  Moreover  the  developmental  disturbance 
may  very  well  be  congenital  if  it  first  manifests  itself  at  the  age  of  puberty. 

^  Guggenheimer  states  that  in  two  cases  of  eunuchoidism  he  found  hj^perglobulia.  He  mentions, 
moreover,  that  in  these  cases  after  the  injection  of  adrenalin  there  never  occurred  an  increase  of 
erythrocytes,  but  even  diminution  of  these.  He  says  that  he  could  not  "corroborate"  the  hyper- 
globulia  after  injection  of  adrenalin  as  observed  by  Berklll,  Schweiger,  and  myself.  This  expres- 
sion seems  to  me  out  of  place.  We  have  never  asserted  that  we  saw  hyperglobulia  after  the  injec- 
tion of  the  doses  of  adrenalin  used  in  man.  The  hyperglobulia  observed  by  us  in  the  dog  after 
larger  doses  had  already  declined  after  twenty-four  hours.  Guggenheimer,  however,  tested  very 
small  doses  of  adrenalin  twenty-four  hours  after  injection.  The  individual  values  for  the  ery- 
throcytes in  Guggenheimer' s  case  also  varied  appreciably  in  the  daj-s  uninfluenced  by  adrenalin. 


EUNUCHOIDISM  4II 

It  is  also  conceivable  that  traumatic  and  infectious  insults  in  early  youth  may 
damage  the  sexual  glands  and  thus  lead  to  eunuchoidism.  This  is  especially 
true  of  mumps,  perhaps  also  of  scarlet  fever,  measles,  etc.  We  shall  meet 
with  these  etiological  factors  again  in  the  consideration  of  late  eunuchoidism. 
Xot  rarely,  eunuchoidism  is  hereditary.  The  case  concerned  in  direct  repro- 
duction can  be  only  the  Hghtest  cases,  those  principally  associated  with  obes- 
ity in  childhood.  On  the  contrary,  it  is  conceivable  that  cases  that  do  not 
reproduce  may  now  and  then  crop  up  in  a  family.  Such  a  famihal  occur- 
rence has  been  reported  by  Sainton.  Of  five  living  brothers  and  sisters, 
three  were  eunuchoids  and  besides  this  an  uncle  and  great  uncle. 


Grandfather 

Great-uncle 

+ 

Uncle 

+ 

Mother 

9                          9 
Died  early                   ], 

+ 

cf 

+ 

+ 

cf 

Very  noteworthy  is  the  observation  that  eunuchoidism  and  chlorosis 
can  occur  in  the  same  family  {Tandler  and  v.  Noorden)  (see  also  Obser- 
vation H). 

Differential  Diagnosis. — Differential  diagnostically,  infantilism  and  h3rpo- 
physial  dystrophy  come  chiefly  into  consideration.  The  former  in  the 
pure  forms  shows  retention  of  the  childish  dimensions.  Also  the  psyche 
remains  infantile;  but  the  psyche  of  male  eunuchoids  although  mannish, 
can  hardly  be  called  childish.  Peretz  and  Wolf  are  wrong  in  their  attitude 
against  the  delimination  of  the  eunuchoid  type.  When  they  call  eunuchoid- 
ism a  pure  form  of  infantilism,  they  are  confused  as  to  the  meaning  of  the 
diseases.  Both  the  female  individuals  thatPerefe  describes  are  to  my  mind 
not  eunuchoids,  but  infantiles  (see  Chapter  XII,  InfantiUsm).  Naturally 
there  occur  also  mixed  forms  of  infantilism  and  eunuchoidism,  hence  cases 
of  infantihsm  in  which  the  development  of  the  sexual  glands  not  only  remain 
at  a  childish  stage,  but  their  function  is  much  more  seriously  disturbed. 
It  must  not  be  forgotten  that  normally  the  interstitial  glands  functionate 
also  in  children,  even  if  a  subordinate  degree  only.  Such  cases  show  in 
addition  to  the  infantile  features  also  more  or  less  distinct  eunuchoid  dimen- 
sions and  the  typical  distribution  of  fat  such  as  is  not  a  feature  of  true  in- 
fantihsm. The  four  female  cases  of  Wolk  are  not  true  eunuchoids.  One 
of  them  is  apparently  a  true  dwarf,  the  others  are  cases  of  infantihsm,  or 
at  least  transitional  cases  which  tend  nevertheless  more  toward  infantilism. 
The  differentiation  from  hypophysial  dystrophy  is  on  the  whole  not 
difficult.  Common  to  both  are  the  genital  disturbance  and  the  association  of 
fat  distribution  or  obesity.  Hence  there  are  an  eunuchoid  and  h^-pophysial 
form  of  dystrophia  adiposo-genitalis.  The  two  forms  are  dift'erent  from  each 
other : 


412  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

1.  By  the  growth  in  height.  In  the  hypophysial  form,  so  far  as  it  sets  in 
in  childhood,  is  found  pronounced  inhibition  of  growth;  in  the  eunuch- 
oidal  form  is  found  even  tallness,  or  at  least  no  growth  disturbances. 

2.  Eventually  through  the  behavior  in  metabolism.  In  the  severe  forms 
of  hypophysial  dystrophy  the  fundamental  exchange  is  usually  dis- 
tinctly reduced  in  the  end;  in  the  eunuchoid  form  the  reduction  is 
perhaps  not  considerable  enough  to  become  demonstrable.  The 
answer  to  these  questions  will  depend  on  further  investigations. 

3.  Through  the  cerebral  manifestations  in  hypophysial  dystrophy. 
Here  in  most  cases  are  found  signs  of  a  hypophysial  tumor  or  of,  at 
least,  a  tumor  in  the  hypophysial  region,  or  at  least  signs  of  increased 
brain  pressure.  One  should  not  forget,  however,  that  cases  of  eunuch- 
oidism at  the  time  of  puberty  not  at  all  rarely  complain  of  headaches; 
and  occasional  vomiting  may  occur  (two  casesunder  my  observation). 
In  such  cases  the  X-ray  examination  of  the  sella  is  very  important. 
At  all  events  there  are  also  processes  that  may  destroy  the  hypophysis 
without  distinctly  altering  the  sella  and  producing  symptoms  of  brain- 
pressure  ;  for  examples  gummata  or  chronic  inflammations.  Such  proc- 
esses indeed  set  in  after  completed  development.  Hence  here  comes 
into  consideration  the  differentiation  from  late  eunuchoidism  or  from 
multiple  ductless  glandular  sclerosis. 

The  blood  examination  in  the  hypophysial  as  well  as  the  eunuchoid  form 
mostly  shows  a  pronounced  mononucleosis.  Hence  here  there  is  no  dis- 
tinguishing factor.  We  can  at  most  say  that  in  the  hypophysial  form,  at  least 
in  the  severe  cases,  the  hemoglobin  and  the  erythrocyte  count  are  often  more 
markedly  reduced. 

Prognosis  and  Treatment.^Very  important  is  the  observation  of  Tandler 
and  Grosz,  that  in  the  eunuchoidism  that  sets  in  early,  developmental  dis- 
turbances of  the  sexual  glands  are  often  only  temporary  (prepubertial  eunuch- 
oidism). Hence  such  cases  may  be  improved.  One  of  my  cases  showed 
such  a  condition.  At  the  sixteenth  year  (Observation  Sch)  the  voice  had 
changed,  the  genitalia  had  developed  almost  normally,  but  as  yet  there  had 
occurred  no  pollutions.  In  these  cases  the  obesity  is  only  improved  for  the 
abnormal  distribution  of  fat  still  exists.  In  such  cases  we  would  recognize 
the  developmental  disturbances  later  in  life  by  the  distribution  of  fat,  and 
probably  also  by  the  hair  condition.  Also  it  is  very  probable  that  in  these 
cases  the  function  of  the  sexual  glands  disappears  prematurely.  Case  II 
of  Josef  son  and  Lundquist  seems  to  point  in  this  direction. 

Rapid  improvements  have  been  reported  from  the  thyroidin  treatment. 
A  pert  mentions  a  case  complicated  with  cryptorchidism  in  which  after  one- 
half  year's  treatment  with  thyroidin,  the  penis  had  distinctly  grown,  the 
testicles  had  lowered,  and  the  weight  had  increased  about  2K  kg. 

Also  Parhon  and  Mihailesko  report  a  similar  case  in  a  fourteen-year-old 


LATE    EUNUCHOIDISM  413 

youth  with  left-sided  inguinal  cryptorchidism  and  obesity;  under  thyroidin 
treatment  the  genitals  took  on  a  rapid  development. 

There  is  no  doubt  that  we  are  often  able  to  improve  with  thyroidin  the 
fat  types  of  obesity.  Thus  for  example  in  Observation  Sch,  there  occurred 
without  limitation  of  diet,  after  the  administration  of  even  small  doses  of 
thyroidin,  a  rapid  reduction  of  3  kg.  in  weight.  A  considerable  improvement 
is  also  reported  by  Lemos  Magelhaes.  In  a  case  of  adipositas  nimia  who 
weighed  160  kg.  there  occurred  under  thyroidin  treatment  a  reduction  of  323^^ 
kg.  Then  intoxication  symptoms  appeared.  I  do  not  feel  justified,  however, 
in  referring  offhand,  as  do  Apert,  Parhon  and  Mihailesko,  the  improvement 
in  the  genital  sphere  to  the  thyroidin  treatment,  or  in  constructing,  because 
of  the  improvement,  an  etiological  connection.  To  me  the  reports  do  not 
seem  convincing  that  these  cases  were  cured  by  thyroidin,  because  as  has  just 
been  mentioned,  there  have  been  sometimes  observed  in  this  growth  period 
improvements  that  are  spontaneous.  But  we  must  accept  a  certain  stimu- 
lating action  of  thyroidin. 

Not  much  has  been  reported  as  to  other  methods  of  treatment.  I  do  not 
know  that  extracts  of  sexual  glands  have  been  used.  As  radium  emanations 
have  a  certain  stimulating  action  on  the  sexual  glands — Freund  and  /  saw 
several  times  through  radium  treatment  an  increase  of  the  potency,  a  re- 
currence of  the  periods  at  the  climacteric  or  an  aggravation  of  dysmenorrheic 
complaints — in  one  case  (Observation  Sch)  I  used  the  radium  emanation, 
perhaps  with  good  results.  Such  a  result  is  to  be  expected  only  in  youthful 
cases.  In  another  case  (Observation  H,  twenty-eight  years  old),  who  on 
account  of  his  joint  affection  was  treated  for  a  long  time,  all  action  on  the 
sexual  glands  remained  absent. 

The  transplantation  of  the  sexual  glands  has  not  to  my  knowledge  been 
tried  in  the  treatment. 

4.  Late  Eunuchoidism 

Historical. — The  first  excellent  description  of  this  disease  we  find  in 
Larrey  in  his  "  Campagne  d'Egypte:  de  I'atrophie  des  testicules."  Larrey  ob- 
served in  several  soldiers  who  had  followed  the  campaign  in  Eg3Tpt  with 
Napoleon  and  later,  in  soldiers  of  the  Imperial  Guard,  simultaneously  with 
gradually  occurring  atrophy  of  the  testicles  with  retrogression  of  the  penis, 
disappearance  of  the  libido  and  the  potency,  falling  out  of  the  pubic  and  ax- 
illary hairs,  development  of  a  falsetto  voice,  and  certain  alterations  of  intelli- 
gence and  psyche.  Larrey  sees  the  cause  of  the  disease  in  the  deleterious  in- 
fluences of  the  climate,  or  in  sexual  abuse  or  in  alcoholism.  Lately  interest 
has  again  been  turned  toward  this  subject  by  Gandy  who  described  three 
cases,  that  he  termed  infantilism  reversif  ou  tardif.  Of  Gandy' s  cases  I 
would  regard  two  as  typical  cases  of  late  eunuchoidism.  The  third  belongs 
to  multiple  ductless  glandular   sclerosis.     Gandy   seeks   the   cause   of  the 


414  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

affection  chiefly  in  a  dysthyroidism,  while  Claude  and  Gougerot  describe  a 
series  of  cases  that  they  refer  to  an  insufflsance  pluriglandulaire  endocrinienne. 
Cordier  and  Rehattii  treat  the  subject  in  a  large  study  of  these  cases;  they 
again  uphold  the  designation  "infantilisme  regressif  type  Gandy.'' 

Recently  I  have  published  a  study  on  this  subject  in  which  I  pointed  out 
that  the  manifestations  in  this  disease,  so  far  as  they  connected  with  the 
genitals,  are  like  those  of  eunuchoidism;  and  I  selected  from  the  group  the 
pure  cases  of  "late  eunuchoidism"  ["Spateunuchoidismus"]  from  late  eu- 
nuchoidism which  is  only  the  partial  manifestation  of  a  very  complex  clinical 
picture. 

Definition. — /  term  "late  eunuchoidism"  a  clinical  picture  that  comes  about 
by  the  fact  that  in  an  already  matured  organism  in  which  also  the  functions  of  the 
sexual  glands  have  attained  their  full  development,  there  occurs  atrophy  of 
the  accessory  genital  apparatus  {in  man  retrogression  of  the  penis,  scrotum,  the 
prostate,  etc.;  in  woman  the  labia  majora  and  the  uterus),  and  retrogression  of 
the  secondary  sexual  characters  {mustache,  beard,  hairiness  of  the  axillce  and  the 
pubis,  the  trunk  and  the  extremities).  Moreover  there  develop  more  or  less 
distinct  collections  of  fat  on  the  breasts,  the  mons  Veneris,  and  the  hips,  and 
often  certain  alterations  of  the  psyche.  The  typical  eunuchoidal  alterations  of 
the  skeleton  can  no  longer  go  on  developing,  especially  where  the  develop- 
ment of  the  skeleton  has  been  already  closed  off;  that  is  where  the  epiphysial 
junctures  have  already  united. 

There  is  regularly  found  a  high-grade  afection  of  the  sexual  glands,  that  must 
be  regarded  as  the  cause  of  the  manifestations  described. 

Case  Reports. — I  have  already  treated  in  my  publication  the  case  histories 
of  this  affection  somewhat  in  detail.  Since  the  time  I  wrote  my  article  I  have 
found  still  more  cases  in  the  older  and  newer  literature.  As  I  would  describe 
the  clinical  picture  in  detail  and  delimit  it  as  precisely  as  possible,  I  will  here 
make  a  complete  report  of  thccase  histories.  Then  I  shall  classify  the  cases 
according  to  their  etiology,  as  nearly  as  possible.  Moreover,  I  would  here 
state  that  the  position  of  a  series  of  cases  is  still  uncertain.  I  shall  come  back 
to  these  cases  in  the  consideration  of  multiple  ductless  glandular  sclerosis, 
and  here  set  forth  only  those  cases  which  I  regard  as  pure  cases  of  late  eu- 
nuchoidism or  at  least  as  cases  in  which  the  manifestations  of  late  eunuchoid- 
ism stand  quite  in  the  foreground. 

A.  Cases  that  depend  on  a  traumatic  foundation. 

Observation  of  A  chard  and  Demanche. — Sixty-cight-j^ear-old  man.  Pale  tinge,  the 
skin  of  the  entire  body  pale  and  dry.  Hair  of  head  abundant,  skin  of  the  face  and  trunk 
and  extremities  completely  bald.  Eyebrows  sparse.  The  breasts  not  essentially  enlarged. 
The  scrotum  small,  both  the  testicles  small,  the  cremasteric  reflexes  very  weak.  Intelli- 
gence normal.  Easily  excitable  disposition;  at  the  twenty-fifth  year  of  life,  the  man  had 
sustained  an  injury,  due  to  the  tread  of  a  foot,  in  the  scrotal  region.  The  testicles  had  be- 
come swollen,  as  the  result  of  the  injury,  and  later  atrophied.     Beard  and  cranial  hair, 


LATE    EUNUCHOIDISM  415 

that  previously  had  been  abundant,  became  at  the  same  time  always  sparser,  the  muscu- 
lar strength  decreased,  a  certain  amount  of  libido  was  retained,  but  ejaculations  had  never 
occurred. 

Observations  of  GaUavardin  and  Rebattu. — Twenty-six-year-old  man,  174  cm.  tall, 
looks  like  a  fifteen-year-old  youth.  Preponderance  of  the  lower  length  over  the  upper 
length  (femur  +  tibia  =  90 J^^  cm.).  The  distal  epiphyses  of  the  radius  and  ulna  have 
as  yet  not  united.  The  voice  that  previously  had  been  mannish,  is  now  shrill,  the  skin 
is  white  and  delicate,  scrotum  and  penis  are  very  small  (as  in  a  six-  to  ten-year-old  boy). 
At  eighteen  and  one-half  years  of  age  the  man  had  received  a  violent  knock  in  the 
scrotal  region,  after  which  for  three  hours  he  was  unconscious.  After  this  there  devel- 
oped a  considerable  swelling  of  the  testicles  and  bloody  suffusion  of  the  skin  of  the 
scrotum;  these  phenomena  disappeared  after  three  months.  Later  the  testicles  became 
small,  the  penis  atrophied,  the  secondary  sexual  characters  and  the  libido  disappeared, 
and  complete  impotence  appeared.  The  photograph  accompanying  the  report  of  the 
case  shows  well  the  eunuchoidal  fat  distribution. 

Observation  of  Cordier. — Twenty-nine-year-old  man,  looks  like  an  eighteen-year-old 
youth.  Genitalia  and  prostate  markedly  atrophic,  secondary  sexual  characters  and  libido 
have  almost  disappeared.  The  man  married  at  the  age  of  twenty-five  years,  is  the 
father  of  one  child.  At  twenty-five  and  one-half  years  a  trauma  that  affected  the  tes- 
ticles. Gardual  falling  out  of  the  hairs  of  the  mustache,  the  beard  since  then  has  become 
very  sparse,  marked  reduction  of  libido. 

Observation  of  Stieda. — Thirty-year-old  man.  At  the  age  of  fifteen  both  testicles 
bruised.  From  then  on  the  testicles  became  gradually  smaller,  he  first  remained  behind 
in  growth  and  then  grew  appreciably  between  the  twentieth  and  thirtieth  years.  The 
voice  was  only  somewhat  rough,  and  the  potentio  coeundi  remained,  although  there  was 
no  ejaculation  of  semen.  The  mammary  glands  grew  somewhat  in  circumference. 
According  to  his  statement  a  growth  about  the  size  of  a  thaler  appeared  at  their  site 
on  each  side.  The  man  remained  beardless,  there  was  hair  on  the  mons  Veneris  but  the 
upper  border  of  this  hair  was  horizontal.  Height  175  cm.,  the  extremities  were  remark- 
ably long,  the  breadth  of  the  shoulders  was  slight,  the  pelvis  broad,  the  larynx  small, 
internal  and  external  genitalia  had  remained  behind  in  development.  The  testicles 
were  about  the  size  of  beans,  the  epididymises  were  about  just  as  large. 

Observation  of  Riedinger. — The  patient  in  his  twenty-first  year  suffered  a  severe  injury 
in  which  the  anterior  perineal  region  was  bruised  and  the  scrotum  torn,  and  the  testicles 
and  prostate  severely  injured.  The  penis  had  previously  been  of  normal  size  (examined 
by  Rieder).  Erections  were  still  possible  the  first  year  after  the  injury,  but  there  were  no 
signs  of  ejaculations.  Now  erections  only  very  seldom,  no  sexual  intercourse  any  more. 
The  man  is  163  cm.  tall,  the  lower  extremities  (from  the  trochanters  down)  are  86  cm. 
long,  the  skin  is  pale  in  color,  the  skin  of  the  face  lax  and  wrinkled.  He  appears  much 
older  than  he  is.  The  skin  is  otherwise  lax  and  flabby.  He  is  very  thin;  the  accom- 
panying photograph  allows  one  readily  to  recognize,  however,  the  abundance  of  fat  in  the 
breasts  and  on  the  mons  Veneris.  The  penis  is  6  cm.  long,  reduced  in  all  its  dimensions. 
The  pubic  hairs  are  very  sparse  and  the  upper  border  of  the  pubic  hairiness  is  horizontal. 
The  hairs  in  the  axillary  and  anal  region  are  also  sparse.  No  beard  (before  the  injury 
there  was  a  beard).  The  voice  is  mannish,  lately  a  goiter  has  developed.  The  sella 
turcica,  as  the  author  kindly  informed  me  in  a  written  communication,  is  not  enlarged. 
Own  Observation  LII. — Forty-two-year-old  man,  rather  corpulent,  breasts  very  rich 
in  fat,  mons  Veneris  and  hips  somewhat  more  rich  in  fat.  Sparse  hairiness  of  the  axillae. 
Genitalia  rather  well  covered  with  hairs.  Both  the  testicles  as  large  as  peas,  very  soft, 
the  scrotum  small,  without  tension,  cremasteric  reflexes  absent.  Bilateral  scars  in  the 
inguinal  regions  as  the  result  of  operation. 


41 6  THE  DISEASES  OF  THE  SEXUAL  GLANDS 

Four  years  ago,  after  operation  for  bilateral  inguinal  hernia  there  developed  on  each 
side  an  enormous  hematoma,  which  after  some  time  disappeared.  Only  a  few  weeks  after- 
ward the  patient  noticed  diminution  of  potency,  which  later  disappeared  entirely  for  a  time. 
The  libido  did  not  disappear  entirely,  later  erections  were  again  possible  and  coitus  was 
performed  a  number  of  times  per  month.  According  to  statement;  only  a  slight  ejacula- 
tion occurred. 

The  cause  of  the  atrophy  of  the  testicles  in  these  cases  may  very  well  be  regarded  as  a 
circulatory  disturbance,  whether  through  injury  of  the  arteries,  or  compression  due  to 
shrinking  of  scar  tissue,  whereby  damage  was  done  to  the  nutrition  of  the  testicles. 

B.  Cases  that  depend  on  an  orchitis  due  to  syphilis,  gonorrhea,  or  mumps. 

Perhaps  some  of  the  cases  described  by  Larrey  belong  to  this  group. 

Observation  of  Coffin. — Male  individual,  after  bilateral  luetic  orchitis  the  testicles 
shrank  to  the  size  of  beans.  The  voice  became  higher,  obesity  developed,  the  beard 
fell  out,  the  muscular  power  diminished,  erections  and  ejaculations  ceased,  the  penis 
became  smaller,  finallv  to  the  size  of  that  of  a  six-  or  seven-year-old  child.  The  breasts 
became  larger. 

Observation  of  Charcot. — Soldier.  After  bilateral  mumps,  orchitis,  atrophy  of  the  tes- 
ticles to  the  size  of  beans.  Libido  disappeared,  complete  impotence,  the  breasts  in- 
creased in  size. 

Observation  of  Lereboullet. — Twenty-seven-year-old  man,  skin  pale,  eunuchoid  form, 
breasts  well  developed,  penis  and  testicles  very  small,  impotence.  Beard  absent,  the 
patient  was  formerly  very  potent  and  the  beard  well  developed.  The  voice  mannish. 
At  twenty-four  years,  mumps  with  bilateral  orchitis,  later  gradual  atrophy  of  the  testicles. 

Observation  of  Dalche. — Thirty-six-year-old  man.  Color  of  face  pale,  hair  of  beard 
abundant.  Hairs  of  beard,  axillae  and  genitalia,  are  entirely  absent.  Testicles  very 
atrophic,  libido  absent,  complete  impotence,  intelligence  weak,  forgetfulness,  tendency 
to  weep,  apathy;  often  chills.  At  twenty  years  lues,  at  thirty  years,  bilateral  orchitis, 
since  that  time  development  of  the  genital  atrophy.  Later  also  slight  swelling  of  the 
legs  and  the  face.  Polyuria.  In  this  case  the  eunuchoidism  is  certainly  in  the  fore- 
ground. But  in  addition  there  exist  symptoms  (and  indeed  chiefly  symptoms  of  fail- 
ure) on  the  part  of  the  other  ductless  glands. 

Observation  of  Diipre. — Forty-five-year-old  man.  Abundance  of  hair  on  head.  ^Mus- 
tache  much  reduced,  very  little  pubic  hair,  pallor  of  the  face;  penis  and  testicles  small, 
soft,  libido  absent,  impotence.  Formerly  gonorrhea  and  syphilis.  At  the  thirtieth 
year  gradual  testicular  atrophy  and  development  of  the  symptoms  described. 

Observation  of  Candy. — Forty-six-year-old  man.  Color  of  face  pale-yellowish,  sec- 
ondary sexual  characters  very  sparingly  developed.  Genitals  markedly  atrophic,  some 
collection  of  fat  on  the  trunk.  Impotence.  Formerly  entirely  normal,  lues  at  the  thirty- 
third  year.  About  this  time  beginning  of  the  retrogression  of  the  genitalia,  and  secondary 
sexual  characters,  temporary  polyuria  (in  the  thirty-sixth  year),  also  temporary  swelling 
of  the  face. 

Observation  of  Candy. — Forty-two-year-old  man.  Face  very  pale,  wax-like,  skin  of 
the  forehead  arranged  in  fine  parallel  folds,  skin  of  the  trunk  delicate,  voice  monotonous, 
no  hair  at  all  on  lips  or  trunk,  penis  and  testicles  very  small,  prepuce  long  and  folded, 
cremasteric  reflexes  absent,  no  libido;  impotence,  memory  somewhat  weakened,  apathy, 
blood-pressure  reduced.  "At  thirty-two  years  of  age  bilateral  gonorrheal  orchitis;  from 
about  this  time  began  atrophy  of  the  genitalia  and  impotence.  At  the  twenty-ninth 
year  states  that  he  is  somewhat  stronger;  pad-like  swelling  of  the  skin  of  the  face,  the 
hands,  and  the  back  of  the  feet. 


LATE    EUNUCHOIDISM 


417 


Gandy  regards  this  case  as  " dysthyreoidie  +  dysorchidie."  I  believe,  however,  that, 
in  spite  of  this,  late  eunuchoidism  stands  in  the  foreground. 

Apparently  also  the  observation  of  Foges  belongs  here.  After  bilateral  luetic  orchitis 
there  developed  a  "gynakomastie."  The  mammary  glands  were  removed,  microscopical 
examination  showing  only  fat  and  no  glandular  substances.  Sexual  sensation  was  much 
reduced. 

C.  Cases  of  other  etiology. 

Observation  of  Cordier  and  Francitlon. — Thirty-five-year-old  man.  lysK  cm.  tall, 
lower  length  90^3  cm.  hence  distinctly  predominating.  Epiphyses  united,  eunuchoid 
distribution  of  fat,  skin  pale,  diffuse  pigmentations.  Hairs  representing  beard  absent, 
hair  on  cheeks  sparse,  atrophy  of  the  genitals,  libido  present  but  coitus  rare  and  incom- 
plete. Weakness  of  memory.  Patient  is  quarrelsome,  easily  excited,  slight  anemia  with 
hyperleucocytosis  and  mononucleosis  (phthisis  pulmonalis  is  present,  however).  Typhoid 
fever  at  about  twenty-four  years  of  age.  Before  development  was  entirely  normal  and 
potency  was  normal.  Several  months  after  the  typhoid  gradual  development  of  genital 
atrophy  and  impotence;  temporarily,  also,  complete  loss  of  libido.  Great  bodily  weak- 
ness, that  later  improved.     Since  that  time  increase  in  height  about  3  cm. 

Observation  of  Gougerot  and  Gy. — Fifty-two-year-old  man,  quite  normal  up  to  forty- 
eighth  year  (except  that  he  had  had  gonorrhea) ;  about  this  time  a  hard  to  deiine  acute 
infectious  disease,  after  this  asthenia,  polydipsia,  polyuria,  atrophy  of  the  genitalia,  im- 
potence, loss  of  libido,  retrogression  of  the  secondary  sexual  characters,  pigmentations  on 
the  forehead,  hands  and  feet,  cachexia. 

Observation  of  Galtiard. — Fifty-seven-year-old  man,  face  very  pale,  mustache  and 
beard  very  sparse,  no  hair  in  the  axillae,  scrotum  and  penis  small,  testicles  very  small, 
impotence.  At  fifty-three  years  eczema,  "since  that  time  development  of  the  phenomena 
described." 

Observation  of  Belfield. — In  a  man  twenty-seven  years  old  there  developed  at  the  same 
time  with  a  polyuria  a  "retrograde  puberty,"  atrophy  of  the  testicles  and  the  external 
genitalia,  retrogression  of  the  secondary  sexual  characters,  etc.  The  hair  of  the  head 
remained  abundant.  Examination  took  place  when  the  man  was  thirty-nine  years  old. 
X-ray  showed  sella  turcica  normal.  Thyroidin  therapy  and  later  adrenalin  were  used 
without  results.  Later  was  administered  dried  suprarenal  gland,  containing  both  cortex 
and  medulla.  After  four  months  the  daily  amount  of  urine  had  been  reduced  to  one- 
half.  The  body  hairs  had  grown  distinctly,  the  testicles  were  twice  as  large,  and  coitus 
already  had  been  several  times  performed. 

I  would  here  refer  to  the  observation  of  Josef  son  and  Lnndqiiist  (case  2).  We  can 
regard  this  case  as  a  transition  between  eunuchoidism  and  late  eunuchoidism.  I  have 
described  this  case  in  detail  in  a  previous  section. 

Finally,  more  on  account  of  the  curiosity,  I  will  report  an  observation  described  by 
Hammond.  The  Pueblo  Indians  in  New  Mexico  seem  to  have  cultivated  the  so-called 
mujaderes  for  purposes  of  pederasty.  For  this  purpose  already  fully  developed  men  are 
excessively  masturbated  and  at  the  same  time  are  made  to  ride  enormously.  This  treat- 
ment causes  an  atrophy  of  the  testicles  and  epididymises,  the  penis  becomes  smaller, 
libido  disappears,  the  testicles  are  insensitive  to  pressure,  the  mammae  enlarge,  the  indi- 
viduals become  fat,  the  voice  becomes  higher  and  the  bodily  strength  decreases.  Ham- 
mond himself  has  examined  two  such  individuals.  While  in  many  respects  the  story 
sounds  fabulous  (one  of  the  mujaderes  stated  that  he  had  suckled  children),  the  agree- 
ment with  the  picture  of  late  eunuchoidism  is  so  complete  that  I  had  at  least  to  mention 
the  observation. 
27 


41 8  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

S3miptomatology. — ^Late  eunuchoidism  is  found  almost  exclusively  in 
men.  There  have  been  individual  cases  reported  in  women  but  these  are 
not  pure  cases.  As  we  shall  see  later  they  belong  to  the  group  of  multiple 
ductless  glandular  sclerosis.  The  cause  of  the  disease  in  man  is  either  violent 
trauma  effecting  the  testicles  or  their  vicinity,  or,  as  in  my  case,  probably,  a 
damage  to  both  spermatic  cords  through  shrinking  of  scar  tissue;  or  a  bi- 
lateral high-grade  orchitis  on  a  syphilitic  or  gonorrheal  basis,  or  mumps 
orchitis;  or  it  may  be  due  to  severe  infectious  disease — typhoid  for  example — 
or  to  an  infectious  process  of  an  unknown  nature,  affecting  the  entire  organ- 
ism and  probably  also  the  testicles.  At  the  close  of  these  deleterious  influ- 
ences, or  also  in  certain  cases  quite  spontaneously,  wdthout  distinct  recog- 
nizable cause,  in  individuals  w^ho  previously  had  been  entirely  normally 
developed,  in  whom  especially  the  secondary  sexual  characters  were  com- 
pletely developed  and  in  whom  the  genital  function  has  been  entirely  nor- 
mal—  there  develops  quite  gradually  an  atrophy  of  the  entire  genital  appa- 
ratus and  at  the  same  time  a  retrogression  of  the  secondary  sexual  characters. 

Finally  there  seem  to  be  cases  in  which  there  exists  from  youth  a  certain 
lessened  valuation  of  the  rudiments  of  the  sexual  glands  and  soon  an  exhaus- 
tion (case  of  Josef  son  and  Ltmdquist) . 

The  ages  of  the  affected  individuals  are  very  different.  In  the  case  de- 
tailed the  beginning  of  the  disease  fell  between  the  eighteenth  and  fifty- 
third  years  of  life. 

The  alterations  in  the  genitals  must  be  regarded  as  manifestations  of 
retrogression  and  not,  as  Claude  and  Gougerol  believe,  as  mere  atrophy.  In 
this  view  I  am  entirely  in  accord  with  Gaudy.  The  retrogression  of  the  testi- 
cles may  be  astounding.  The  testicles  are  estimated  as  at  the  size  of  hazel- 
nuts, cherries,  beans,  and  peas.  The  diminution  of  volume  is  naturally  less 
where  connective  tissue  has  formed  at  the  site  of  an  infectious  process;  and 
here  too  there  is  not  such  a  diminution  in  consistence;  in  most  cases  has  been 
emphasized  an  especial  softness.  The  scrotum  can  be  as  small  as  that  of  an 
eight-  to  ten-year-old  boy;  and  it  loses  its  tension  and  its  pigments.  Also  the 
penis  can  reduce  in  size  to  such  an  extent  that  it  looks  like  that  of  an  eight- 
to  ten-year-old  boy.  The  picture  is  therefore  entirely  similar  to  that  of  early 
eunuchoidism.     Also  the  prostate  takes  part  in  the  atrophy. 

We  have  already  described  the  manifestations  that  occur  after  castration 
in  the  matured  woman.  Retrogression  of  the  genitalia  occurs,  mostly  an 
increased  fat-deposit  and  loss  of  pigment,  but  not  a  falling  out  of  the  pubic 
and  axillary  hair.  We  shall  consider  later  under  ductless  glandular  sclerosis 
those  cases  in  which  retrogression  in  the  hairiness  occurs  simultaneously 
with  spontaneous  atrophy  of  the  ovaries. 

In  late  eunuchoidism  the  function  of  the  genitals  suft'ers  severe  damage. 
In  man  complete  impotence  with  entire  incapability  of  cohabitation  can 
occur  under  circumstances.     Libido  is  here  entirely  lost;  but  in  other  cases 


LATE    EUNUCHOIDISM  419 

only  impotence  occurs,  while  libido  remains  in  enfeebled  form.  In  the  formes 
frustes  the  capability  for  cohabitation  still  remains;  except  that  in  these  cases, 
as  Cordier  and  Rehattu  point  out,  much  stronger  stimuli  are  needed  to  induce 
erection.  The  cremasteric  reflexes  are  either  weaker  or  entirely  wanting. 
Hence  the  functional  disturbance  also  corresponds  entirely  with  that  of  early 
eunuchoidism. 

The  same  is  true  for  the  coloration  of  the  face.  The  pallor  of  the  face 
and  the  delicacy  of  the  skin  and  body  are  noted  in  all  cases.  There  is  often 
found  a  yellowish  tinge ;  and  (in  one  case)  folding  of  the  skin  of  the  forehead 
(as  in  eunuchs) .  Puf&ness  of  the  skin  of  the  face  is  very  rare  indeed  among 
the  cases  reported. 

The  hair  of  the  head  remains  abundant,  but  as  a  rule  is  rather  dry.  (The 
cases  with  patches  of  alopecia  do  not  belong  to  pure  late  eunuchoidism.) 

In  severe  cases  the  hair  of  the  body  falls  out  entirely.  The  mustache, 
that  previously  may  have  been  very  luxuriant,  falls  out  entirely  or  at  least 
thins  out  very  much.  The  same  is  true  of  the  beard;  often  is  found  the  state- 
ment that  the  patients  who  previously  had  to  shave  several  times  a  week, 
shave  much  less  frequently.  Thinning  out  of  the  lashes  and  the  eyebrows 
does  not  indeed  belong  to  the  pure  picture  of  this  disease.  Also  the  trunk 
and  the  extremities  may  become  entirely  bald.  The  axillary  hairs,  the 
hairs  on  the  scrotum,  the  perineum,  and  on  the  root  of  the  penis,  may  fall 
out  altogether. 

Very  important  for  the  comprehension  of  the  disease  picture  are  the  al- 
terations of  the  form.  As  has  previously  been  mentioned,  it  is  in  itself  sug- 
gestive that  where  the  beginning  of  the  disease  falls  at  an  age  where  the  total 
epiphysial  junctures  are  closed,  a  development  of  the  eunuchoidal  skeletal 
type  is  no  longer  possible.  Of  especial  importance,  therefore,  are  the  observa- 
tions of  Gallavardin  and  Rehattu,  of  Cordin  and  Francillon,  and  of  Stieda.  In 
the  first  case  a  youth  of  eighteen  and  one-half  years  old  suffered  a  knock  in  the 
scrotal  region,  and  in  the  second  the  beginning  of  the  disease  lay  in  the  twen- 
tieth year.  In  the  first  case  there  was  only  a  suggestion  of  the  eunuchoidal- 
skeletal  type  (predominance  of  the  lower  length  over  the  upper  length),  and 
the  epiphysial  junctions  that  close  at  a  later  period  were  still  open  at  the 
twenty-sixth  year.  In  the  second  case  there  was  a  further  growth  of  about 
3  cm.  at  the  twenty-fourth  year.  The  case  of  Stieda^s  sustained  a  trauma  in 
the  fifteenth  year  of  life.  He  first  remained  behind  in  grow^th  and  then  grew 
appreciably  between  the  twentieth  and  the  thirtieth  years.  Here,  therefore, 
the  epiphysial  junctions  had  remained  open  abnormally  long.  Here  also 
there  came  about  the  development  of  the  eunuchoidal  dimensions. 

The  influence  on  the  weak  parts  is  noted  more  frequently.  In  many  cases 
the  statement  is  made  that  there  appeared  at  the  beginning  of  the  disease 
an  adiposity;  in  other  cases  that  the  breasts  had  become  fatty,  or  the  hips 
rounded,  or  that  the  mons  Veneris  had  become  richer  in  fat.     In  several 


420  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

cases,  in  which  the  typical  distribution  had  not  been  noted  especially,  it 
could  be  recognized  in  the  illustrations  that  accompany  the  reports. 

In  the  majority  of  cases  it  is  furthermore  stated  that  the  voice  which  had 
previously  been  mannish,  altered  in  the  course  of  the  disease.  A  falsetto 
voice  did  not  develop,  as  in  eunuchs  and  early  eunuchoids,  but  the  voice 
placement  was  high  and  the  voice  shrill. 

In  the  pure  cases  there  is  no  alteration  of  the  intelligence.  The  apathy, 
[mental]  heaviness,  forgetfulness,  that  are  stated  to  have  occurred  in  indi- 
vidual cases,  may  well  be  referred  to  the  general  prostration  following  several 
general  infectious  diseases  or  perhaps  to  a  sHght  myxedematous  component. 
We  shall  again  see  such  manifestations  under  multiple  ductless  glandular 
sclerosis.  In  pure  cases  the  statements  as  to  alterations  of  the  moral  and 
psychical  attitude  are  on  the  contrary  very  frequent;  statements  that  such 
individuals  like  early  eunuchoids,  are  psychically  more  easily  excited,  and 
given  to  sudden  anger  and  to  lying.  In  two  cases  also  has  been  noted  tem- 
porary polyuria  {Gougerot  and  Gy.  and  Dalche).  In  the  first  case  the  late 
eunuchoidism  came  after  an  acute  infectious  disease,  in  the  second  after  lues. 
We  shall  often  meet  with  these  symptoms  in  the  consideration  of  multiple 
ductless  glandular  sclerosis.     Perhaps  it  is  of  hypophysial  origin. 

Are  we  now  justified  in  separating  out  these  cases  as  an  especial  clinical 
formation  and  giving  it  the  name  "late  eunuchoidism?"  As  has  been  men- 
tioned, Gandy  regards  them  as  "dysthyreodie  +  dysorchidie."  Gallavardin 
and  Rehattu  express  themselves  more  in  favor  of  [in  affection  of]  the  sexual 
glands,  Cordier  and  Rehattu  distinguish  between  an  "infantilisme  regressif 
myxedemateux  et  non  myxedemateaux."  Claude  and  Gougerot  finally  group 
all  these  cases  under  "  insuflisance  pluriglandulaire."  The  confusion  can,  I 
think,  readily  be  overcome  if  we  place  in  the  foreground  the  classification  of 
these  cases  according  to  their  etiological  factor,  and  separate  out,  before 
everything  else,  those  cases  which  have  the  value  of  experiments,  namely, 
the  traumatic.  Where  acute  infectious  diseases  or  noxi  of  a  more  general 
nature  have  led  to  degeneration  of  the  sexual  glands  it  is  very  well  intelligible 
that  also  other  ductless  glands  can  suffer  damage,  and  that  other  features 
often  hard  to  define  become  associated  with  the  picture  of  a  disease  that  is 
due  to  falling-out  of  the  sexual  gland. 

As  to  the  significance  of  thyroid  insufficiency  in  this  disease  picture,  we 
can  become  clear  on  this  point,  if  we  have  recourse  to  the  experiments.  If 
in  an  individual  who  has  attained  complete  maturity,  the  thyroid  gland  is 
completely  extirpated,  there  come  about  disturbances  of  the  genital  function, 
but  never  any  such  retrogression  of  the  genitaha  as  has  been  just  described. 
The  thyroprivic  disturbance  of  the  genital  function  can  be  promptly  over- 
come by  thyroidin  medication,  while  all  statements  are  in  accord  that 
thyroid  medication  does  not  improve  the  disturbance  of  sexual  glandular 
function  in  late   eunuchoidism.     In  spontaneous  myxedema  of  adults  the 


LATE    EUXITCHOIDISM 


421 


behavior  in  these  respects  is  not  always  as  clear  as  in  operative  myxedema. 
It  should,  however,  be  considered  that  the  disease  process  that  -in  this  con- 
dition is  responsible  for  the  sclerosis  of  the  thyroid  gland  very  readily  and 
very  often  involves  other  ductless  glands,  and  that  here  we  are  no  longer 
dealing  with  mere  action  at  the  distance. 

Can  wx  show  by  experimentations  the  significance  of  the  sexual  glands 
for  this  chnical  picture  in  a  clean  and  clear-cut  fashion?  To  answer  this  we 
must  have  recourse  to  the  known  experiments  of  Ancel  and  Boiii)i.  In 
male  grown  animals  the  ligation  or  transection  of  the  vas  deferens,  or  patho- 
logical stenosis  of  the  exit-ducts  of  the  sperm,  leads  to  degeneration  of  the 
germinative  part  of  the  sexual  glands,  while  the  interstitial  substance  is 
retained.  The  animals  become  sterile  but  they  are  not  impotent,  and  retain 
their  masculine  appearance.  If.  however,  the  ■" interstitial  glands"  are 
brought  to  degeneration  the  animals  lose  their  masculine  appearance  and 
become  similar  to  castrates.  In  this  manner  there  is  therefore  produced  an 
experimental  late  eunuchoidism.  I  refer  moreover  to  late  castrates  whom  I 
have  described  above.  The  same  value  for  the  pathogenesis  is  afforded  by 
the  very  numerous  cases  of  pure  traumatic  late  eunuchoidism;  they  show  that 
severe  injuries  of  the  male  genitalia  may  lead  to  the  full  symptom-complex  of 
late  eunuchoidism;  also  in  these  cases  there  does  not  exist  the  slightest  basis 
for  regarding  the  condition  as  a  primary  aft'ection  of  the  other  ductless 
glands.  The  question  as  to  whether  the  loss  of  both  sexual  glands  leads 
regularly  to  the  development  of  late  eunuchoidism  does  not  seem  to  me  en- 
tirely solved  by  the  material  up  to  the  present  time,  although  I  regard  it  as 
very  likely.  Widal  and  Lutier  have  reported  a  case  with  marked  testicular 
atrophy,  in  which  the  manifestations  of  late  eunuchoidism  did  not  seem  to  be 
present.  Cordier  and  Rehattu  discuss  the  possibility  whether  in  these  cases 
there  were  still  present  functionally  capable  islands  of  Leydig's  interstitial 
cells  or  ectopic  sexual  glandular  tissue. 

Much  less  clear  are  the  alterations  in  women.  That  premature  meno- 
pause and  hyperinvolution  of  the  uterus  through  repeated  births  or  pro- 
longed lactation  does  not  lead  to  any  change  in  the  secondary  sexual  char- 
acters is  readily  intelligible,  as  there  need  not  be  associated  with  the  retro- 
gression of  the  follicular  apparatus  a  retrogression  of  the  interstitial  substance. 

On  the  contrary  it  is  really  not  intelligible  why  the  loss  of  the  whole 
ovaries  exercises  such  little  influence  on  the  axillary  and  pubic  hair.  The 
few  cases  of  pronounced  regression  of  this  hair  seem  to  me  to  belong  under 
the  caption  multiple  ductless  glandular  sclerosis. 

The  differential  diagnosis  has  especially  to  consider  the  diseases  of  the 
hypophysis  that  first  develop  in  later  years  after  the  attainment  of  the  com- 
plete cessation  of  growth  and  complete  maturity  of  the  body.  In  this  case 
there  is  no  disturbance  of  growth,  as  occurs  in  the  difi'erential  diagnosis 
between  the  eunuchoid  and  the  hypophysial  dystrophia  adiposa-genitahs. 


422  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

Where  symptoms  of  brain-pressure  are  present  and  the  X-ray  shows  altera- 
tions of  the  sella  turcica,  the  diagnosis  is  at  once  cleared  up.  Sometimes 
difficult,  however,  is  the  delimitation  from  atrophic  and  inflammatory 
sclerotic  processes  in  the  hypophysis.  Perhaps  points  of  differential  diag- 
nostic value  can  be  obtained  from  the  examination  of  the  respiratory  gaseous 
exchange  and  of  the  purin  metabolism.  The  history  also  ought  to  be  im- 
portant; the  fact  that  the  patient  has  sustained  a  luetic,  gonorrheal,  or 
mumps  orchitis  should  at  any  rate  lead  to  the  suspicion  of  late  eunuchoidism. 
The  differential  diagnosis  with  respect  to  multiple  ductless  glandular  sclerosis 
will  be  considered  later. 

The  treatment  has  not  up  to  the  present  yielded  anything  reassuring. 
That  thyroid  medication  fails  is  indeed  only  too  comprehensible.  But  also 
the  administration  of  sexual  glandular  substances  has  led  to  only  transitory 
results,  or,  as  in  the  case  of  Dalche,  led  to  improvement  of  symptoms  that 
probably  were  not  to  be  referred  to  the  lack  of  the  sexual  glands  (forgetful- 
ness,  general  weakness,  chills).  In  the  valuation  of  therapeutic  results,  we 
should  not  forget  that  in  certain  cases  spontaneous  improvement  is  possible, 
such  as  also  occurs  in  early  eunuchoidism. 

5.  Treatment  of  Sexual  Glandular  Insufficiency 

The  drug  therapy  of  sexual  glandular  insufficiency  has  as  yet  had  in  man 
no  decisive  results.  The  feeding  with  testicular  substance  is  but  little 
carried  out,  and  the  reports  as  to  the  result  of  injection  of  sexual  glandular 
extracts  disagree.  Spermin  (Poehl)  may  have  a  certain  stimulating  action 
on  the  nervous  system,  but  profound  symptoms  of  insufficiency  are  hardly 
improved  thereby. 

In  want  of  a  better  treatment,  thyroid  treatment  has  been  recommended 
— a  therapy  that  plays  a  part  in  the  treatment  of  all  ductless  glandular  affec- 
tions, to  a  certain  extent  indeed,  erroneously.  In  eunuchoid  obesity,  thyroid 
medication  has  on  the  whole  a  good  result  and  is  certainly  to  be  recom- 
mended if  it  be  employed  with  necessary  caution.  It  is  also  conceivable 
that  through  stimulation  of  metabolism  often  a  certain  furthering  influence 
is  exerted  on  the  sexual  glands,  but  we  cannot  expect  decisive  results  as  to 
this  point.  In  such  cases  treatment  with  hypophysis  tablets  seems  to  be  en- 
tirely valueless.  I  do  not  know  whether  anybody  has  as  yet  employed 
pituitrinum  infundibulare.  As  I  have  mentioned  already,  perhaps  employ- 
ment of  radium  emanations  would  be  of  some  value,  but  as  yet  no  experiments 
with  them  have  been  reported.  I  shall  not  go  further  into  the  question  of  the 
other  roborant  and  tonic  treatment  methods. 

The  organotherapy  of  the  symptoms  due  to  loss  rest  on  a  much  broader 
experience  as  far  as  is  concerned  with  woman.  The  medication  with  ovarian 
substances  was  introduced  by  Regis  and  has  been  especially  recommended  by 


TREATMEXT    OF    SEXUAL    GLAXTDULAR    IXSUFFICIEXCY  423 

Jacobi,  Chrobak,  Landau,  and  others.  Various  preparations  have  come  into 
the  market;  oophorin  tablets,  ovaraden,  ovarin,  ovarial  tabloids,  etc.  Ordi- 
narily 3  to  6  tablets  are  administered  daily.  As  has  been  mentioned.  Lou'v 
and  RicJiter  found  in  their  experiments  a  stimulation  of  the  respiratory 
metabolism;  but  this  result  seems  to  be  inconstant,  as  other  investigators 
did  not  find  it.  Also  there  did  not  always  occur  an  improvement  in  the 
nervous  symptoms.  Bucura  points  out  that  this  may  be  due  to  the  unre- 
liability of  the  preparations  used.  He  beheves  that  it  is  not  a  matter  of 
indifference  whether  the  preparations  are  obtained  from  the  ovaries  of  young 
or  old  animals,  and  whether  they  are  taken  during  the  rutting  season  or  the 
interval.  He  mentions  experiments  with  the  milk  of  rutting  animals.  As 
3^et  the  involution  of  the  uterus  after  castration  cannot  be  prevented  by  the 
use  of  ovarian  substances  {Jentze  and  Beutner).  Fraukel  proceeding  from  his 
view  that  the  corpus  luteum  possesses  an  internal  secretion,  has  introduced 
lutein  tablets  into  therapy. 

Very  promising  are  the  experiments  on  transplantation  of  the  sexual 
glands.  Rihhert  was  the  first  who  succeeded  in  transplanting  testicles. 
Foges,  after  autotransplantation  of  the  testicles  in  young  fowls,  saw  rather 
good  development  of  secondary  sexual  characters.  Steinach  succeeded  with 
the  same  experiment  in  rats  and  guinea-pigs.  The  interstitial  cells  and  the 
SertoWs  cells  were  retained,  but  seminal  cells  were  entirely  absent.  I  do 
not  know  whether  homiotransplantation  of  the  testicles  has  succeeded.  If 
it  were  to  succeed,  a  favorable  influence  on  eunuchoidism  would  not  be  impos- 
sible. The  transplantation  of  the  testicles,  epididymis,  and  vas  deferens,  and 
therewith  the  possibility  of  semen  production,  is  still  the  task  of  the  future. 

Much  more  noteworthy  are  the  experiments  T\dth  transplantation  of 
the  ovaries.  Here  also  the  successful  experiment  is  that  of  autotransplanta- 
tion which  was  done  by  Rihhert.  Knauer  then  showed  that  in  grown  rabbits 
involution  of  the  uterus  could  be  prevented  by  the  autotransplantation.  An 
essential  progress  was  made  by  the  experiment  of  Halhan.  who  in  new-born 
guinea-pigs  transplanted  the  ovaries  under  the  skin.  After  one  and  one-fourth 
3'ears  there  was  still  present  parenchyma  capable  of  functionating.  Graafian 
follicles  and  even  mature  ova  had  developed  and  the  tube  that  had  been 
transplanted  at  the  same  time  had  matured  in  normal  manner.  The  breasts, 
as  well  as  the  uterus,  had  developed  normally.  In  the  castrated  control 
animals  the  breasts  remained  rudimentary  and  the  genitalia  were  markedly 
h}'poplastic.  In  woman,  also,  transplantation  has  occasionally  been  followed 
by  good  results  in  operations  on  the  genitalia.  It  is  true  that  transplants 
often  show  regressive  manifestations,  but  a  part  of  the  parenchyma  may, 
however,  stiU  be  retained,  and  on  account  of  this  the  involution  of  the  uterus 
and  the  nervous  symptoms  due  to  the  loss  are  prevented.  In  autotrans- 
plantation in  the  neighborhood  of  the  tube,  even  maturation  of  the  o\'um 
and  pregnancy  have  occurred. 


424  THE    DISEASES    OF    THE    SEXUAL    GLAXDS 

Still  more  significant  are  the  experiments  with  homiotransplantation  of 
the  ovaries.  I  refer  to  the  collected  statistics  of  Xovak.  It  is  true  that  in 
most  cases  the  result  lasted  only  for  a  short  time,  but  in  animal  experiments 
numerous  results  of  longer  duration  including  maturation  of  the  ovum  and 
conception  have  occurred.  On  experiments  in  man.  I  mention  the  two  cases 
that  follow.  Cranner  transplanted  into  a  twenty-one-year-old  woman,  who 
had  never  menstruated  and  who  possessed  rudimentary  mammas,  the  ovary 
of  an  osteomalacic  woman.  Menstruation  then  set  in  and  the  breasts  de- 
veloped. Still  more  remarkable  is  a  case  of  Halliday-Crom.  In  this  case 
amenorrhea  had  set  in  after  labor  and  symptoms  of  absence  developed. 
The  small  cystic  ovaries  were  removed  and  a  foreign  ovary  implanted. 
The  woman  again  menstruated  four  months  after  the  operation,  and  four 
years  after  the  operation  she  conceived  and  bore  a  normal  child.  This  case 
was  earnestly  discussed  before  the  Edinburgh  Obstetrical  Society,  and 
cannot  well  be  denied.  There  is  indeed  in  this  case  no  doubt  that  if  there 
has  been  no  error  of  observation,  this  woman  bore  the  child  of  another  woman. 
Serious  objections  might  be  raised  against  such  procedures  on  ethical  and 
forensic  grounds. 

m.  HYPERGENITALISM 

Definition. — We  have  come  to  know  hypergenitalism  already  in  the 
chapters  on  the  hypophysis  and  in  the  consideration  of  suprarenal  cortical 
tumors.  There  are  also  cases  of  premature  development  of  the  genitalia 
associated  with  temporary  excessive  development  of  the  organisms,  in  which 
the  epiphysis  or  the  suprarenal  cortex  do  not  come  into  consideration  as 
etiological  factors,  but  in  which  we  must  assume,  with  great  probability,  a 
primary  disturbance  of  the  sexual  glandular  function  on  the  sense  of  a  pre- 
mature occurrence  or  an  excessive  increase. 

Pathologico -anatomical  Findings. — A  portion  of  these  cases  show  malig- 
nant tumors  of  the  sexual  glands.  Xcuratli  collects  five  cases  from  the  litera- 
ture, four  ovarian  tumors  (two  established  at  autopsy,  two  on  operation)  and 
one  testicle  tumor  (operation).  In  another  the  sexual  glands  were  described 
as  only  extraordinarily  large.  I  must  state  that  in  two  cases  hydrocephalus 
was  reported.  One  of  the  cases  was  reported  by  Wetzler;  also  in  a  case  of 
Pellizzi's  did  there  exist,  besides  pronounced  hypergenitalism  and  excess- 
ive growth,  hydrocephalus  with  convulsions.  Whether  these  were  cases 
of  primary  hypergenitahsm  cannot  in  the  present  state  of  our  knowledge  be 
answered. 

Symptomatology. — The  premature  sexual  development  is  found  in  both 
boys  and  girls.  Xeurath,  who  has  written  an  excellent  essay  on  this  subject, 
quotes  forty-three  cases  of  premature  sexual  development  in  boys.  In 
such  individuals  an  excessive  development  of  the  genitalia  may  occur  al- 
readv  in  the  first  vear  of  life. 


HYPERGEXITALISM  425 

I  quote  the  following  examples.  The  case  of  Bernhardt-Ziehen  was  that  of  a  three- 
year-old  boy  in  whom  an  enormous  growth  had  set  in  at  the  eighteenth  month.  At  two 
years  the  pubic,  axiUary,  and  beard  hairs  were  present.  At  two  and  one-half  years  the  legs 
had  hair  on  them;  he  was  103  cm.  tall,  the  circumference  of  the  skuU  was  53  cm.,  the  body 
weight  49.5  kg.  He  looked  like  a  seven-  or  eight-3-ear-old  boy.  He  was  again  examined  at 
the  age  of  eight  years.  He  was  then  138  cm.  tall  (116  cm.  is  the  height  for  this  age).  The 
circumference  of  the  skull  was  56.5  cm.  The  sexual  parts  were  developed  like  those  of  a 
grown  man.  He  looked  as  if  he  were  twenty-five  to  thirty  years  old.  His  intelligence  was 
fairly  weU  developed,  he  was  lively,  showed  inclination  for  the  female  sex,  but  otherwise  his 
demeanor  was  childish.  As  another  example  I  cite  the  case  of  Hudovernig  and  Popovicz. 
In  a  later  investigation  of  Hudovernig  the  boy  was  five  and  one-half  years  old;  at  one  and 
one-half  years  he  sustained  a  febrile  disease  (meningitis).  The  abnormal  growth  had 
existed  since  that  time.  He  was  137  cm.  taU  and  weighed  ^^.^  kg.,  this  corresponding  to 
the  age  of  fifteen  or  sixteen  years.  The  penis  is  9  cm.  long,  the  testicles  very  well  de- 
veloped. The  psyche  is  infantile.  The  intelligence  is  rather  behindhand.  Skull  and 
face  were  rather  asymmetrical.  The  X-ray  examination  showed  that  the  ossification  was 
as  well  advanced  as  that  of  a  fifteen-  or  sixteen-year-old  boy.  Also  the  skuU  bones  were 
well  developed,  and  the  sella  turcica  seems  to  have  been  enlarged,  although  the  observation 
is  not  convincing.  The  boy  was  first  treated  with  thjToidin  tablets  or  with  thyroidin 
tablets  plus  potassium  iodide.  This  did  not  afi'ect  the  excessive  growth.  Later  ovarian 
tablets  were  administered.  This  time  the  growth  was  somewhat  less  (only  3.1  cm.  in  nine 
months  as  compared  with  5  cm.  in  the  six  months  of  the  first  period  and  5  cm.  in  the  ten 
months  of  the  second  period).  In  the  third  period  the  boy  seemed  to  have  become  psy- 
chically more  quiet.  Hudovernig  assumes  that  the  ovarian  tablets  have  retarded  the 
excessive  growth.  I  doubt  this.  If  we  calculate  the  growth  per  month  we  obtain  for  the 
first  period  0.95  cm.,  for  the  second,  0.5  cm.  and  for  the  third.  0.3  cm.  There  is  hence 
found  a  gradual  decrease  of  the  excessive  growth,  which  surely,  as  we  shall  see  later, 
is  to  be  referred  to  the  gradual  closing  of  the  epiphyses.  Finally  I  would  mention  the 
case  of  Stone,  which  is  especially  interesting  from  the  fact  that  also  the  father  of  the  boy 
showed  a  premature  development. 

These  cases  all  have  in  common  the  premature  and  excessive  development 
of  the  genitalia  and  of  the  secondary  sexual  characters,  premature  change  of 
voice,  and  the  excessiA'e  body  development.  Already  in  the  first  year 
there  occur  erections,  ejaculation — Pellizzi  demonstrated  spermatozoa  in  his 
cases — and  eventually  premature  sexual  instinct.  The  development  of  the 
internal  genitalia  often  hurries  the  development  of  the  whole  body.  As  far 
as  the  latter  is  concerned,  the  osseous  system  and  the  musculature  are  mostly 
afi'ected  in  like  manner.  There  therefore  occurs  a  transitory  gigantism; 
as,  hov^^ever,  the  epiphysial  closure  is  rather  hastened,  the  body  growth  finally 
attained  is  not  abnormal,  but  mostly  rather  small.  The  psychic  and  intel- 
lectual development  of  such  individuals  do  not  keep  pace  with  the  body 
development;  they  for  the  most  part  show  a  childish  demeanor,  corresponding 
with  their  age,  which  demeanor  has  a  characteristic  stamp  only  through  the 
premature  sexual  life.  The  assumption  of  such  cases  as  primary  hyper- 
genitalism  is  often  uncertain  without  autopsy  findings,  although  such  a  pri- 
mary hypergenitalism  may  be  made  secure  by  operation  in  certain  cases. 
I  mention  especially  the  case  of  Sacchi.     It  was  that  of  a  nine-year-old  boy 


426  THE  DISEASES  OF  THE  SEXUAL  GLAXDS 

who  had  developed  normally  until  his  fifth  year;  in  that  year  an  excessive 
growth  and  especially  a  premature  development  of  the  genitalia  and  of  the 
secondary  sexual  characters  set  in;  at  the  same  time  there  developed  a  tumor 
of  the  left  testicle;  at  nine  years  of  age  the  boy  weighed  44  kg.  and  was  143 
cm.  tall.  The  lower  length  was  77  cm.  Hence  the  boy  showed  childish  di- 
mensions, and  was  in  this  respect  different  from  other  true  gigantism  which, 
as  we  shall  see  later,  show^s  either  normal  or  eunuchoid  dimensions.  The 
testicular  tumor,  which  was  an  alveolar  carcinoma,  was  removed.  One 
month  after  the  operation  the  beard  hairs  fell  out  and  the  abnormal  hairiness 
of  the  extremities  retrogressed;  the  hairs  on  the  mons  Veneris  remained.  The 
penis  became  smaller,  the  previously  low  voice  became  childish,  and  the 
pollutions  and  erections  ceased. 

In  the  female  sex  such  cases  are  mostly  described  under  the  title  men- 
struatio  praecox.  The  older  literature  is  found  in  Kussmaul  and  v.  Haller. 
Neuratli  counts  eighty-three  cases  from  the  literature.  The  external  genitalia 
develop  in  an  abnormal  manner,  mostly  more  strongly  than  the  internal. 
The  secondary  sexual  characters  (hairiness,  etc.)  and  the  development  of  the 
mammas  are  always  abnormally  premature.  As  in  the  male  sex,  excessive 
growth  of  the  body  is  found  to  be  more  or  less  pronounced.  Also  the  den- 
tition, the  change  of  teeth,  and  the  appearance  of  the  bone  nuclei  and  the 
closure  of  the  epiphysial  junctures  is  premature. 

I  cite  the  following:  The  case  of  Geinitz  was  one  of  menstruatio  praecox  in  an  eighteen- 
month-old  girl.  The  uterus  had  attained  the  size  of  a  twelve-  to  fourteen-year-old 
girl.  The  case  of  Klein,  of  menstruatio  praecox  (two  and  one-half  3'ears),  the  vulva  had 
grown  to  the  size  of  that  of  a  fourteen-year-old  girl.  Stacker  describes  twin  sisters,  of 
whom  one  had  been  larger  since  birth.  In  the  first,  menstruation  began  before  the  end 
of  the  first  year.  The  flow  occurred  regularly  every  four  weeks,  lasting  three  days.  At 
eight  years  of  age  the  child  had  the  size  and  appearance  of  a  twelve-year-old  girl;  she 
measured  139  cm.  and  weighed  34?4  kg.,  while  the  twin  sister  was  121  cm.  tall  and 
weighed  20  kg.  The  case  of  Xeurath  was  that  of  a  six-year-old  girl  who  exceeded  in  size 
and  weight  her  eight-year-old  sister.  The  ossification  conditions  corresponded  to  those 
of  the  tenth  or  eleventh  year.  Recently  there  has  been  reported  a  case  of  Wolf  concerning 
a  girl  four  years  and  one  month  old.  The  size  had  been  large  since  birth.  The  child 
had  menstruated  since  the  second  year.  She  looks  like  a  seven-j'ear-old  girl.  The  hair 
of  the  head  is  long.  The  height  is  121  cm.,  the  weight  26  kg.,  the  span  width  114. 5  cm. 
(hence  potentized  childish  dimensions).  The  intelligence  corresponds  to  the  age.  The 
mammae  are  very  well  developed.  The  mons  Veneris  is  covered  with  hair.  The  ossi- 
fication corresponds  to  that  of  a  ten-year-old  child.  Especially  instructive  is  the  case  of 
V.  Haller.  In  this  the  menstruation  set  in  at  the  age  of  two  years;  at  the  age  of  eight 
the  girl  became  pregnant  and  shortly  afterward  the  excessive  growth  stopped.  She 
lived  to  be  seventy-five  years  old.  This  case  shows  that  premature  closure  of  the  epiph- 
yses may  also  occur  in  the  female  sex.  Finallj-  the  case  of  Riedel  shows  that  in  certain 
cases  a  primarj'  hypergenitalism  may  be  demonstrated  also  in  females.  In  this  case  of 
precocious  menstruation  (six-year-old  child)  the  uterus  was  the  size  of  a  seventeen-year- 
old  girl.  There  was  a  sarcoma  of  the  ovaries ;  on  the  removal  of  the  sarcoma,  the  menstrua- 
tion ceased. 


CHLOROSIS  427 

Treatment. — Up  to  the  present,  the  treatment,  as  far  as  tumors  were 
demonstrable,  has  been  surgical  operation.  In  many  cases,  as  is  shown  in 
the  above  reports,  the  results  were  remarkable.  Whether  X-ray,  radium 
irradiations,  or  mesothorium  irradiations  have  been  tried  as  yet  in  certain 
cases,  I  do  not  know.  Also  in  cases  without  demonstrable  tumors  it  is 
conceivable  that  injections  of  thorium  X  or  actinium  X  might  induce  an 
inhibition  of  the  abnormal  sexual  glandular  development  and  thus  influence 
the  premature  development  of  the  organism. 

IV.  CHLOROSIS 

The  circumstance  that  the  beginning  of  chlorosis  always  falls  at  the  time 
of  puberty  or  during  the  time  of  maturation  of  the  female  organism  following 
puberty,  together  with  the  circumstance  that  in  chlorosis,  disturbances  in 
the  genital  sphere  are  found  almost  regularly,  shows  that  this  disease,  at 
least  to  a  certain  extent,  belongs  in  the  chapter  on  the  sexual  glands.  Opin- 
ions are  at  variance  in  regard  to  the  nature  of  the  functional  disturbances. 
Therefore  I  avoid  placing  chlorosis  in  one  of  the  divisions  of  hypogenitalism 
or  hypergenitalism  and  give  it  a  position  by  itself. 

Historical. — Virchow  on  the  ground  of  pathologico-anatomical  findings 
assumed  a  congenital  deficient  development  of  the  vascular  system.  Im- 
memann  supposed  a  weakness  of  the  blood-forming  organs  that  is  in  part 
congenital  and  associated  with  the  hypoplasia  of  the  vascular  system,  and 
in  part  acquired  and  temporary.  The  disease  begins  in  puberty  because 
at  this  time  especial  demands  are  made  in  blood-forming  apparatus,  v. 
Bunge  places  in  the  center  of  the  pathogenesis  a  disturbance  in  the  iron 
metabolism.  The  maternal  organism  gives  to  the  child  organism  a  very 
great  amount  of  iron.  This  is  stored  up  not  during  pregnancy  but  already 
at  the  time  of  puberty,  whereby  there  occurs  a  poverty  of  the  blood  in  hemo- 
globin. Zander  regards  the  cause  of  chlorosis  as  a  disturbance  of  the  absorp- 
tion of  iron,  other  authors  as  chronic  constipation,  and  as  gastroptosis  through 
the  wearing  of  tight  corsets,  etc.  Basing  his  views  on  the  theory  of  Immer- 
mann,  v.  Noorden  for  the  first  time  explains  a  disturbance  of  the  activity  of 
the  ductless  glands  as  essential  for  the  coming  into  existence  of  chlorosis. 
According  to  i'.  Noorden  chlorosis  depends  on  an  in  part  congenital,  in  part 
acquired,  weakness  of  the  blood-forming  organs,  in  consequence  of  which 
there  occurs  in  the  period  of  sexual  ripening  disturbances  in  the  blood- 
formation  proceeding  from  the  female  sexual  organs.  Normally  impulses 
flow  from  the  female  sexual  glands  to  the  blood-forming  organs.  Loss  or 
weakening  of  the  internal  secretion  of  the  ovaries  leads  to  chlorosis. 

Grawitz  sees  the  cause  of  chlorosis  in  a  disturbance  of  the  relation  of  hquid 
interchange  between  blood  and  tissues.  This  depends  on  deficient  function 
of  the  vasomotors.     He  therefore  regards  chlorosis  as  a  neurosis. 

Very  recently,  Morowitz,  on  the  ground  of  observations  in  which  the  rest 


428  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

of  the  chlorotic  symptom-complex  is  associated  with  an  approximately  normal 
blood  condition,  upholds  the  view  that  the  blood-changes  in  chlorosis  con- 
stitute only  a  symptom  and  not  the  essence  itself  of  the  disease;  he  points 
to  the  frequency  of  thyroid  glandular  swelling  and  believes  the  cause  to  be 
a  disturbance  in  the  reciprocal  action  of  the  ductless  glandular  system. 
Kottman  observes  that  there  is  a  deficient  iron-assimilation  on  account  of  a 
weakening  of  the  internal  secretion  of  the  ovaries.  Finally  we  mention  the 
theory  of  Cliarrni  and  Villcmin  that  chlorosis  is  a  menstrual  autointoxication. 
Villemin  assumes  in  addition  that  the  internal  secretion  of  the  corpus  luteum 
possesses  hemolytic  properties. 

Symptomatology. — Chlorosis  is  a  disease  that  inclines  very  much  toward 
relapses.  The  first  attack  of  chlorosis  usually  occurs  between  the  fourteenth 
and  twentieth  years  of  life.  Cases  of  so-called  tardive  chlorosis  (Hayem, 
Riedcr)  are  extraordinarily  rare.  Lately  also  cases  of  infantile  chlorosis  have 
been  described  {Rist,  Hutinel,  Stoltzner,  el  al.).  Because  of  the  uncertain  con- 
nection with  these  cases  with  true  chlorosis,  v.  Noorden  proposed  for  these  cases 
the  name  chlorotoid.  Also  the  connections  of  the  extraordinarily  rare  cases 
of  conditions  similar  to  chlorosis  occurring  in  the  male  sex  (for  example, 
the  cases  of  FormanoU,  Ferrari.  Byrom  Bramwell)  are  contested  by  most  of 
the  later  authors,  v.  Xoordcn  and  v.  Jagic  believe  that  in  such  cases  we  are 
dealing  with  sexual  neurasthenics  who  are  insufticiently  nourished.  A  great 
role  in  chlorosis  is  played  by  heredity.  Often  many  sicknesses  are  found  in 
the  family  of  the  patient.  In  rare  cases  there  is  observed  in  the  same  family 
simultaneous  occurrence  of  chlorosis  and  of  prepubertal  eunuchoidism 
[Tandler,  v.  Xoordcn;  confer  also  Observation  LI). 

Chlorosis  usually  sets  in  with  a  series  of  subjective  complaints;  attention 
is  attracted  to  the  color  of  the  face.  These  symptoms  consist  in  ready 
fatigability,  cardiac  palpitations  on  slight  bodily  exertions,  slight  dyspnea, 
headache,  sensations  of  cold — especially  tendency  to  cold  hands  and  feet — ■ 
eventually  seeing  black,  flickers  before  the  eyes,  ear  noises,  vertigo,  fainting- 
spells,  pressure  in  the  gastric  region,  nausea,  etc. 

Examination  of  the  heart  often  shows  in  advanced  cases  slight  broaden- 
ing, soft  systolic  murmurs,  the  known  humming-top  murmur  over  the  jugular, 
furthermore  in  a  great  number  of  cases  acceleration  of  the  pulse,  great  ex- 
citability of  the  cardiac  activity  and  of  the  vasomotors.  Further  is  found 
a  marked  laxity  of  the  arteries  (crural  double  tone).  According  to  the 
investigations  of  BiJiler  and  v.  Xoordcn  there  is  always  a  reduction  of 
blood-pressure. 

Breathing  is  mostly  somewhat  accelerated  and  superficial,  with  high 
position  of  the  diaphragm. 

As  far  as  the  digestive  tract  is  concerned,  should  be  mentioned  that  there 
is  frequently  a  slight  degree  of  hyperacidity.  According  to  v.  Xoordcn, 
constipation  is  not  much  more  frequent  than  in  normal  girls.     The  respira- 


CHLOROSIS  429 

tory  gas  exchange  is  usually  slightly  increased.  The  condition  of  nutrition 
is  as  a  rule  not  bad.  Investigations  as  to  the  assimilation  limits  for  carbohy- 
drates gave  an  increase,  or  at  least  no  decrease.  After  the  ingestion  of  150 
gm.  of  grape-sugar,  there  never,  in  the  experiments  of  :'.  Xoorden  and  v. 
Jagic,  occurred  glycosuria  except  in  one  case  that  at  the  same  time  showed 
symptoms  of  Basedow's  disease.  Also  Chatin  came  to  the  same  result.  It 
should  further  be  mentioned  that  not  rarely  chlorotics  show  a  higher  level  of 
their  body  temperature. 

In  not  very  rare  cases  there  are  found  pigmentations  of  the  skin. 

The  examination  of  the  urine  shows  no  abnormal  constituents.  Also 
the  products  of  destruction  of  hemoglobin  are  not  eliminated  in  abnormal 
amount. 

I  now  enter  on  a  description  of  the  blood  findings;  on  account  of  the 
poverty  in  hemoglobin  there  occurs  in  the  severe  cases  a  greenish-pale 
facial  color,  that  has  given  to  the  disease  its  name.  There  are.  however, 
numerous  cases  that  on  account  of  the  reddening  of  the  cheeks  make  a  florid 
impression.  Here  the  disease  is  unmasked  by  a  close  examination  of  the 
mucous  membranes  and  careful  examination  of  the  blood.  The  chlorotic 
blood-finding  is  characterized  by  a  relatively  very  marked  poverty  of  the 
blood  in  hemoglobin  and  a  relatively  slight  reduction  of  the  erythrocyte 
count.  Hemoglobin  amounts  as  low  as  50  per  cent,  are  very  frequent,  those 
and  as  low  as  30  per  cent,  not  rare.  When  there  is  high-grade  poverty  of 
the  hemoglobin  there  is  found  more  or  less  distinct  poikilocytosis;  and  in 
addition  isolated  nucleated  erythrocytes.  In  the  lighter  forms  the  count  of 
the  red  blood  cells  is  normal  or  only  slightly  reduced,  only  in  the  severe 
forms  do  reductions  as  low  as  60  per  cent,  occur.  In  the  severe  cases  the 
specific  gravity  of  the  blood  is  markedly  reduced,  while  that  of  the  serum  is 
essentially  unafi'ected.  With  regard  to  the  leucocytes  there  is  a  slight 
relative  mononucleosis. 

Recently,  as  was  mentioned  at  the  beginning.  Moroi^'itz.  has  called  at- 
tention to  the  fact  that  in  rare  cases  that  otherwise  show  the  symptom-com- 
plex of  chlorosis,  the  blood  is  found  to  be  normal  or  nearly  normal.  Already 
Laache  had  described  such  cases,  also  several  statements  have  been  made  by 
0.  Xaegeli  and  Granitz.  while  lately  Seller .  Groag.  Dubuikojf.  and  others  have 
described  such  cases.  Handmann  even  found  twenty-three  cases  with  normal 
blood  findings  among  forty-four  cases  of  chlorosis. 

It  is  furthermore  very  noteworthy  that  the  investigations  so  far  made  as 
to  the  quantity  of  blood  in  chlorosis  have  shown  a  plethora.  While  accord- 
ing to  the  investigations  of  Smith  the  total  amount  of  blood  in  normal  in- 
dividuals is  about  5  per  cent,  of  the  total  body  weight,  this  author  found  in 
chlorotics  with  29-50  per  cent,  hemoglobin  the  blood  amount  to  be  7.5 
per  cent,  and  14.3  per  cent.  The  lower  the  hemoglobin  percentage,  usually 
that  much  larger  the  amount  of  blood.     PI  esc  h   and  Oerum   using  other 


430  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

methods  came  to  a  like  result.  It  should  further  be  noted  that  in  pernicious 
anemia  Smith  and  Plcsch  found  subnormal  values  [for  the  quantity  of  blood]. 

In  connection  with  this  subject  it  might  be  well  to  mention  the  altera- 
tions in  the  water  metabolism  that  are  observed  in  chlorotics.  v.  Romberg, 
V.  Xoorden  and  Rethers  frequently  observed  in  chlorotics  a  tendency  to  the 
retention  of  water,  while  on  the  other  hand  we  often  see  under  the  influence 
of  iron-therapy  a  rapid  loss  of  weight  with  moderate  polyuria.  As  has  been 
mentioned,  products  of  decomposition  of  hemoglobin  are  not.  in  chlorosis, 
eliminated  in  the  urine.  Therefore  we  cannot  regard  an  increased  destruc- 
tion of  the  blood-coloring  matter  as  a  cause  of  the  poverty  in  hemoglobin. 

Not  at  all  rarely  the  thyroid  gland  shows  a  swelling.  Giudiceandrea, 
Archangeli  and  Bastianelli  found  it  in  half  the  cases.  Handmann  found  it 
in  twenty-four  times  among  forty-four  cases,  three  times  with  distinct 
Basedow's  symptoms,  v.  Xoorden  and  v.  Jagil  report  an  interesting  case  in 
which  the  development  of  the  anemia  was  associated  with  a  swelling  of  the 
thyroid  gland  and  on  a  relapse  led  to  an  acute  Basedow's  that  lasted  for 
several  days.  As  the  statements  as  to  the  involvement  of  the  thyroid  increase 
in  so  astonishing  a  manner  (since  the  time  that  attention  has  been  directed  to 
the  fact) ,  we  must  ask  ourselves  whether  the  pseudocJilorosis  described  by 
Fr.  V.  Midler  does  not  stand  in  an  intimate  relation  with  true  chlorosis. 
V.  Midler  states  that  in  regions  where  goiters  are  frequent,  there  are  not 
rarely  found  pale,  readily  fatigable,  girls  with  abnormally  irritable  heart- 
action,  in  which  manifestation  of  Basedow's  disease  later  became  more 
distinctly  conspicuous. 

Finally  I  come  to  a  description  of  the  alterations  of  the  genitalia,  after 
which  I  shall  add  some  remarks  as  to  the  disease's  pathogenesis.  I  shall 
try  to  separate  those  changes  that  are  due  to  an  alteration  of  the  glands  of 
generation  and  those  to  changes  of  the  interstitial  glands. 

Disturbances  of  development  are  found  in  the  genitalia  in  chlorotics  not 
rarely.  Deficient  development  of  the  external  genitalia,  deficiency  in  the 
prominence  of  the  mons  Veneris,  flat  nates,  small  labia  majora,  while  labia 
minora  and  clitoris  are  uninvolved;  eventually,  narrow  vagina,  faulty  develop- 
ment of  the  uterus,  breasts,  etc.,  are  sometimes  observed.  The  statistical 
reports  of  Stieda,  and  of  //.  W.  Freund  and  ?.  Xoorden  show  that  a  relatively 
larger  percentage  of  chlorotics  have  such  developmental  disturbances  in  more 
or  less  pronounced  manner.  There  are  undoubtedly  a  not  inappreciable  num- 
ber of  chlorotics  whose  genitalia  are  developed  normally.  As  especially  note- 
worthy I  would  emphasize  that  the  hairiness  of  the  genitalia,  the  mons  Veneris, 
and  the  axilla?  corresponds  to  the  age  of  the  individual  and  further  that  a 
delayed  closure  of  the  epiphysial  junctures  and  corresponding  eunuchoid 
dimensions  of  the  body  is  not  to  be  observed  in  chlorosis.  Tandler  states 
on  the  contrary  that  he  has  observed  very  frequently  in  chlorotics  a  very 
frequent  premature  epiphysial  closure,  and  as  a  result  of  this,  an  especial 


CHLOROSIS  431 

short  leggedness  and  also  a  certain  prematurity,  as  shown  by  other  sexual 
characters. 

As  far  as  the  function  of  the  generative  glands  is  concerned,  almost  all 
the  statements  are  concerned  with  menstruation,  while,  as  is  intelligible, 
ovulation  evades  observation.  Disturbances  of  menstruation  are  relatively 
very  common.  I  here  quote  some  examples  from  the  statistics.  According 
to  Stieda  only  seven  chlorotics  among  twenty- three  had  menstruated  regularly. 
According  to  Otten,  among  four  hundred  forty-eight  cases  there  were  only 
one  hundred  eighty-six  who  had  menstruated  regularly  before  and  during 
Ihe  illness.  In  the  first  edition  of  v.  Noorden^s  monograph,  60.7  per  cent,  of 
one  hundred  seventy-three  cases  showed  weakness  of  menstruation.  In  the 
newer  statistics  of  v.  Noorden  and  v.  Jagic  that  embraces  two  hundred 
fifty  cases  this  figure  was  raised  even  to  77.2  per  cent.,  and  twenty-six  of  the 
cases  had  not  menstruated  before  the  onset  of  chlorosis.  There  are,  how- 
ever, cases  with  entirely  normal  menstruation,  and  furthermore  cases  with 
abnormally  strong  menstrual  hemorrhage.  Trousseau  has  described  such 
cases  as  menorrhagic  chlorosis.  In  such  cases  the  ovaries  were  found  to 
be  enlarged  and  there  was  a  great  abundance  of  follicles,  v.  Noorden  and 
V.  Jagic  on  the  basis  of  their  compilation  came  to  the  conclusion  that  in 
chlorosis  menstruation  shows  no  characteristic  behavior. 

Pathogenesis.- — If  we  now  survey  what  I  have  just  said  as  to  the  re- 
lation of  the  sexual  glands  and  the  primary  and  secondary  sexual  characters, 
we  find  it  hard  to  accept  the  theory  that  chlorosis  is  a  functional  disturbance 
of  the  interstitial  glands,  especially  if  we  compare  it  with  those  manifesta- 
tions which  are  described  in  the  rare  cases  of  female  eunuchoidism.  There 
is  indeed  no  doubt  that  in  chlorosis  there  occurs  an  enfeebled  development 
of  the  primary  and  secondary  sexual  characters,  but  in  such  cases  this  is 
mostly  only  of  a  slight  grade,  and  just  the  essential  symptoms  of  failure 
(deficient  hairiness,  delayed  epiphysial  closure)  are  absent  practically  al- 
ways; indeed  on  the  contrary,  according  to  Tandler,  as  has  been  mentioned, 
the  development  points  to  a  degree  of  prematurity.  Also  animal  experi- 
mentations have  as  yet  failed  to  furnish  any  support  for  the  assumption  of 
a  diminished  activity  of  the  interstitial  glands.  According  to  the  investi- 
gations of  Monaro  and  of  Breuer  and  v.  Seiller  the  extirpation  of  the  ovaries 
in  young  dogs  in  a  state  of  development  indeed  leads  to  a  temporary  com- 
mensurate sinking  of  the  amount  of  hemoglobin  and  count  of  erythrocytes, 
never,  however,  to  the  blood  picture  observed  in  chlorosis.  If  I  here  use  the 
methods  that  I  employed  in  the  exposition  of  the  tests  of  the  sexual  glands 
for  separating  the  symptoms  that  depend  on  the  functional  failure  of  the 
interstitial  glands  from  those  to  the  functional  failure  of  the  generative  glands, 
I  may  suppose  a  slight  strengthening  of  the  function  of  the  interstitial  glands; 
it  is,  however,  a  priori  improbable  that  these  stand  in  the  mid-point  of 
the  pathogenesis.     I  believe  that  there  is  applicable  an  hypothesis  that  at 


432  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

least  has  the  advantage  that  it  is  not  contradicted  by  any  of  the  known  facts. 
In  chlorosis,  as  has  already  been  mentioned,  the  behavior  of  menstruation 
shows  nothing  characteristic.  We  find  that  although  in  the  majority  of 
cases  there  is  a  weakening  of  the  menstrual  process,  there  may  be  a  normal 
course  or  an  essential  strengthening.  This  is  what  is  told  to  us  with  regard 
to  menstruation,  but  not  in  regard  to  ovulation.  We  know  only  that  there 
is  no  menstruation  without  ovulation.  It  is  known,  however,  that  under 
circumstances  ovulation  proceeds  without  menstruation,  and  it  does  not  seem 
to  me  that  anything  stands  in  the  way  of  the  proposition  that  under  circum- 
stances it  may  go  on  in  an  increased  or  precipitate  manner.  The  assumption 
of  precipitate  ovulation  in  chlorosis  is,  however,  though  it  seems  fascinating, 
not  at  all  unconditionally  necessary.  To  me  the  assumption  seems  enough 
that  the  violent  revolutions  that  go  on  in  the  feminine  organism  at  the  time 
of  puberty  or  with  the  setting  in  of  a  strengthened  activity  of  the  folHcular 
apparatus  lead  in  nonvigorous  individuals  to  a  temporary  or  longer  con- 
tinued exhaustion  of  the  organism.  We  have  seen  in  the  description  of  the 
physiology  of  the  sexual  glandular  apparatus  that  ripening  of  the  follicle  in 
the  premenstrual  period  leads  lo  a  heightened  vitality  of  the  whole  organ- 
ism. Hence  there  proceed  impulses  from  the  follicular  apparatus  that  spur 
on  all  the  organs  and  especially  the  entire  ductless  glandular  system  to  a 
heightened  activity.  Would  it  not  be  conceivable  that  in  a  predisposed  in- 
dividual, in  whom  these  impulses  are  perhaps  increased  by  precipitate 
ovulation,  there  may  appear  an  exhaustion? 

On  the  basis  of  this  supposition  I  shall  now  proceed  to  analyze  the 
symptom-complex  of  chlorosis.  Let  us  first  consider  the  genital  disturbances. 
The  assumption  of  an  increased  activity  of  ovulation  does  not  seem  to  me 
to  stand  in  contradiction  to  the  diverse  behavior  of  menstruation.  On  the 
one  hand  it  explains  cases  with  increased  menstrual  bleeding,  and  on  the 
other  that  after  a  time  a  feebler  organism  no  longer  reacts  to  every  impulse 
of  the  growing  follicle,  or  at  any  rate  not  with  the  corresponding  altera- 
tions of  the  uterine  mucous  membrane.  It  is  therefore  not  at  all  necessary 
to  consider  that  the  internal  secretion  of  the  corpus  luteum  normally  is 
cast  off  through  menstruation  and  that  with  the  continued  absence  of  men- 
struation with  progressive  ovulation  an  autointoxication  becomes  established 
iVillcmin).  Otherwise  we  would  have  to  have  a  chlorosis  in  every  case  of 
amenorrhea,  and  the  cases  of  chlorosis  with  excessive  hemorrhage  would 
not  be  explicable  at  all.'  An  increased  activity  of  the  folHcular  apparatus 
would  also  exercise  a  certain  reinforcing  action  on  the  function  of  the  in- 
terstitial glands,  thus  explaining  unforcedly  the  symptoms  of  prematurity 
that  are  seen  in  certain  cases. 

Through  my  assumption,  a  case  of  childish  gigantism  with  sexual  pre- 

'  The  assumption  of  Villcmin  depends  in  addition  on  the  incorn.'cl  liypotliesis  that  in  chlo- 
rosis there  is  an  increased  blood  disintegration. 


CHLOROSIS  433 

maturity  and  chlorosis,  observed  by  Hastings  Gifford,  does  not  seem  so  in- 
explicable. The  author  had  observed  this  case  between  the  second  and 
the  eighteenth  years.  Menstruation  began  at  the  age  of  thirteen  months  and 
from  then  on  came  at  irregular  intervals  up  to  the  eighth  year  of  life,  after 
which  it  was  regular.  With  the  menstruation  at  the  thirteenth  month  oc- 
curred also  a  rapid  growth;  at  three  and  one-half  years  of  age  the  child  was 
already  146  cm.  tall  and  weighed  41^^  kg.  X-ray  plates  of  the  hand  showed 
a  development  that  corresponded  to  that  of  an  eight-year-old  girl;  the  sexual 
development  was  that  of  a  thirteen-  to  fourteen-year-old  child.  The  intelli- 
gence had  remained  somewhat  behind.  From  the  sixth  to  the  twelfth  year 
the  girl  was  always  under  treatment  for  recurring  chlorosis.  From  then  on 
recovery  set  in. 

We  have  further  seen  that  in  the  premenstrual  period  the  activity  of  the 
ductless  glands  is  increased,  so  that  there  is  hence  in  chlorosis  either  an  in- 
crease in  the  activity  of  the  ductless  glands,  or,  in  those  whose  activity 
comes  most  in  demand,  an  exhaustion.  Very  significant  in  this  respect 
seems  to  me  the  behavior  of  the  thyroid  gland.  I  refer  to  findings  described 
under  symptomatology  and  the  frequency  of  slight  symptoms  of  Basedow's 
disease.  From  this  standpoint  it  is  indeed  intelligible  that  a  newer  attack 
of  chlorosis,  that  perhaps  takes  place  with  the  maturation  of  a  follicle,  leads, 
when  a  corresponding  disposition  is  present,  to  temporary  symptoms  of 
Basedow's  disease  (see  the  cases  of  v.  N.oorden  and  v.  Jagic). 

A  second  ductless  gland  whose  activity  seems  to  me  to  be  very  significant 
is  the  chromaffin  tissue.  We  have  seen  that  under  normal  conditions  there 
occurs  in  the  premenstrual  period  an  increase  of  blood-pressure,  and  we  have 
expressed  the  opinion  that  impulses  proceed  from  the  ripening  follicle  that 
increase  the  activity  of  the  chromaffin  tissue  and  raise  the  vascular  tonus. 

Plainly  this  organ  can  become  relatively  rapidly  exhausted,  the  ex- 
haustion leading  to  an  influencing  of  the  vasomotor  system  in  the  sense 
of  an  irritable  weakness.  The  laxity  of  the  arteries  as  well  as  the  low  blood- 
pressure  belongs  to  the  constant  symptoms  of  chlorosis.  We  may  indeed  go 
further  and  try  to  explain  the  blood  alterations,  at  least  in  part,  from  this 
point  of  view.  Heightened  tonus  of  the  vessels  leads  to  hyperglobulia 
through  transudation  of  the  plasma  into  the  tissue.  (I  refer  to  the  dis- 
cussions on  the  subject  of  tetany,  and  those  concerning  the  significance  of 
the  chromaffin  tissue  for  the  regulation  and  distribution  of  blood-pressure.) 
It  is  therefore  to  be  expected  that  on  decreased  vascular  tonus  there  will  be 
an  increase  in  the  amount  of  the  blood;  as  the  blood  becomes  thereby  poorer 
in  erythrocytes,  it  is  to  be  assumed  that  erythrocytes  that  are  then  poorer 
in  hemoglobin  are  given  off  to  the  blood  paths.  Just  these  conditions  ob- 
tain in  chlorosis,  increased  amount  of  blood,  slightly  reduced  erythrocyte 
count,  more  markedly  reduced  amount  of  hemoglobin.  In  a  group  of 
cases  the  functional  breadth  of  the  bone  marrow  may  fully  suffice  for  this 


434  THE    DISEASES    OF    THE    SEXL'AL    GLAXDS 

regulation,  in  another  group  it  soon,  according  to  this  \-iew.  becomes  ex- 
hausted, the  exhaustion  leading  to  poverty  in  hemoglobin.  In  addition 
to  this  it  is  possible  that  direct  impulses  go  from  the  follicular  apparatus 
to  the  bone-marrow  and  on  increased  activity  of  the  former  favor  the  ex- 
haustion of  the  latter.  As  according  to  this  hj'pothesis  we  are  deaHng  only 
with  an  exhaustion  due  to  the  large  demands,  it  is  intelUgible  why  in  the 
autopsies  on  cases  of  chlorosis  the  bone-marrow  was  found  to  be  normal 
(Birch-HirscJi field,  Grawitz).  Perhaps  other  symptoms  of  chlorosis  point 
to  a  lessened  valuation  of  the  chromaffin  tissue,  signs  such  as  slight  mono- 
nucleosis, the  not  rare  pigmentation,  and  indirectly  the  high  carbohydrate 
tolerance,  which  up  to  the  present  have  been  observed  by  all  investigators. 
The  investigations  as  to  the  blood  sugar  have  not  as  yet  been  made.  At 
all  events  it  would  not  be  unintelligible  why  chlorosis  develops  just  in  in- 
di\'iduals  with  hypoplasia  of  the  vascular  system,  which,  as  is  known,  is  asso- 
ciated with  hypoplasia  of  the  chromaffin  tissue;  the  corroboration  of  our 
views  would  be  an  instance  of  the  penetrating  vision  of  the  past-master. 
Vircho-j.-. 

This  h}pothesis  seems  to  me  also  to  explain  why  chlorosis  is  found  al- 
most exclusively  in  the  female  sex.  If  we  were  to  assume  the  insufficiency 
of  the  interstitial  glands,  it  would  be  indeed  unintelligible  why  in  eunuch- 
oidism, in  which  the  symptoms  of  insufficiency  are  so  conspicuous,  we  meet 
\s4th  no  chlorosis.  The  interstitial  glands  have  the  same  function  in  both 
cases;  the  follicular  apparatus  is  something  specific  for  woman.  The  revo- 
lutions that  take  place  in  the  female  at  the  time  of  maturity  are  different 
from  those  that  occur  in  man  and  are  much  more  powerful. 

The  experimental  basis  for  this  view  is  yet  to  be  laid.  Whether  the  im- 
plantation into  young  animals  of  ovaries  taken  in  marked  o\'ulation  will  be 
able  to  produce  a  picture  similar  to  chlorosis,  is  at  all  events  questionable; 
just  as  castration,  which  according  to  the  xiev,'  set  forth  would  bring  the 
chlorosis  to  a  standstill  in  a  short  time,  is  impracticable.  We  must,  however, 
consider  whether  a  very  cautious  X-ray  irradiation  of  the  ovaries  would 
not  act  favorably  on  the  chlorotic  process.^  Perhaps  this  view  furnishes  the 
key  for  the  solution  of  the  problem  of  iron  therapy.  As  is  known,  iron  has 
an  almost  specific  action  in  chlorosis,  while  in  the  other  anemic  processes  it 
mostly  fails.  Morauitz  has  concluded  that  the  iron  does  not  act  principally 
on  the  bone  marrow,  but  somewhere  else  in  the  body.     From  the  stand- 

^  I  would  here  call  attention  to  the  later  views  as  to  the  cause  of  uterine  hemorrhages.  Pankow 
pointed  out  that  metritis  and  chronic  endometritis  could  not  be  the  cause  of  the  profuse  men- 
strual hemorrhages.  The  chronic  inflammation  maj-  ver>-  well  be  associated  with  profuse  bleed- 
ing, but  it  does  not  condition  it.  Patikow  seeks  the  cause  rather  in  a  different  functional  size  of 
the  ovaries  conditioned  by  "disturbances  in  the  reciprocal  relations  of  the  ductless  glands  to 
each  other."  Perhaps  the  assumption  of  a  deficient  or  increased  ovulation  would  suffice,  as  the 
climacteric  hemorrhages  have  been  favorably  influenced  by  X-ray  irradiation  (Dodcrlcin), 
which  restricts  the  process  of  ovulation. 


OSTEOMALACIA  435 

point  mentioned,  it  would  be  well  to  investigate  whether  ovulation  or  the 
giving-ofT  of  hormones  is  not  inhibited  by  the  great  amount  of  iron  ingestion. 
At  all  events  it  seems  to  me  that  such  a  specific  influence  of  iron  on  the  ovaries 
is  not  at  all  necessary.  The  difference  of  chlorosis  from  anemia  consists 
in  the  fact  that  the  bone  marrow  in  the  former  is  not  diseased,  but  simply 
gives  out  because  of  increased  demands,  in  the  course  of  w^hich  exhaustion 
the  formation  of  the  red  cells  is  less  affected  than  that  of  the  hemoglobin. 
It  is  thus  readily  understood  why  in  chlorosis  abundant  administration  of  iron 
works  better  than  in  the  anemias.  With  the  increase  of  the  hemoglobin 
may  be  exercised  a  favorable  influence  on  the  entire  organism  and  indirectly 
on  the  sexual  glands. 

Appendix.     Osteomalacia 

In  wa}^  of  an  appendix,  some  remarks  as  to  the  relations  between  osteo- 
malacia and  the  ductless  glands  might  find  place  here.  There  are  no  doubt 
a  number  of,  in  part,  important  facts  that  point  to  the  involvement  of  the 
ductless  glandular  system  in  the  development  of  the  osteomalacic  process; 
the  most  important  of  these  observations  are  the  following: 

1.  Osteomalacia  occurs  almost  exclusively  in  women,  and  indeed,  in  the 
overwhelming  majority  of  cases,  during  pregnancy. 

2.  Castration  leads  very  often  to  a  rapid  cure  or  at  least  a  considerable 
improvement  of  the  osteomalacic  process  (Fehling).  Also  after  labor 
or  after  artificially  induced  abortion,  osteomalacia  tends  to  cure  or 
at  least  to  improve,  just  to  relapse  at  the  next  pregnancy. 

3.  The  curative  or  amehorative  action  of  castration  can  in  such  cases 
enter  in  without  the  interruption  of  the  pregnancy  (cases  of  Cramer, 
Watcher,  CristofoleUo) . 

4.  Frequently  symptoms  are  found  in  osteomalacia  that  point  to  an  in- 
volvement of  the  other  ductless  glands.     Thus  for  instance  osteo- 

•malacia  is  not  rarely  complicated  with  Basedow's  disease  {Latzko},- 
or  with  Basedow's  and  tetany  {Koppen,  v.  Recklinghausen) .  Mohius 
reports  a  case  of  Basedow's  that  later  went  over  into  myxedema,  and 
then  later  acquired  puerperal  osteomalacia.  Moreover,  there  is  found 
in  osteomalacia  frequently,  perhaps  regularly,  a  h}^erplasia  of  the 
parathyroids  (Erdheim,  Strada,  et  al.).  This  hyperplasia  of  the  para- 
thyroids does  not  tend  to  occur  in  senile  osteoporosis. 

5.  In  osteomalacia  the  glycosuric  action  of  adrenahn  and  apparently 
also  its  action  on  the  heart  and  vessels  is  strikingly  slight  {Cristo- 
foletti,  see  also  Reinhardt,  Merletti,  v.  Neusser,  Engldnder,  et  al.).  This 
is  also  true  for  osteomalacia  during  pregnancy,  because  otherwise 
in  pregnancy  the  action  of  adrenalin  is  especially  powerful.  Further- 
more, long-continued  injections  of  adrenalin  in  many  cases  of  osteo- 
malacia have  exerted  favorable  influence   (Rossi).     Cristofoletti  has 


436  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

collected  forty-seven  cases  of  osteomalacia  that  were  treated  with 
adrenalin.     Of  these,  eleven  were  gravid  and  thirty-five  nongravid 
women.     Of  the  gravid  women  45  per  cent,  were  cured,  and  about  18 
per  cent,  improved.     Of  the  nongravid  women  about  17  per  cent,  were 
cured,  and  40  per  cent,  improved. 
6.  In  some  cases  of  osteomalacia  improvement  follows  the  injection  of 
pituitrinum   infundibulare    (Bondi,   Pal).     Lately  Pal   has    reported 
concerning  excellent  influencing  of  the  osteomalacia,  in  two  cases, 
through  injections  of  pituitrinum  glandulare. 
Three  forms  of  osteomalacia  are  to  be  distinguished.     The  puerperal  form 
which  is  by  far  the  most  frequent.     The  rheumatic  form,  which  is  rare, 
which  mostly  does  not  follow  a  severe  course  and  which  occurs  also  in  women 
independent  of   a    preceding   labor;  it   is  also  observed   in  man.     Finally 
the  senile  form. 

The  views  as  to  the  bone  processes  in  osteomalacia  are  many.  One 
group  of  authors  imparts  the  most  important  value  to  the  decalcification  of 
the  completed  bones,  another  group  to  the  apposition  of  especially  calcium- 
poor  bones.  Likewise  is  there  division  of  the  authors  as  to  whether  rachitis 
and  osteomalacia  are  two  different  disease  conditions  or  constitute  one  and 
the  same  disease  process,  that  leads  when  it  develops  in  youth,  to  rickets,  and 
when  it  develops  in  the  fully  developed  organism  to  osteomalacia.  Cristo- 
foletti  sets  forth  the  facts  that  speak  against  the  unitary  theory,  as  well  as 
gross  anatomical  difference:  the  endemic  occurrence  of  osteomalacia  that 
is  independent  of  the  extension  of  the  rachitis,  the  occurrence  in  grown 
people,  and  finally  the  cardinal  symptom  of  osteomalacia,  the  pain,  which  is 
absent  in  rachitis.  The  fact  also  seems  to  me  noteworthy  that  rachitis 
mostly  affects  persons  who  were  not  rachitic  in  youth. 

As  might  be  expected,  investigations  as  to  calcium  metabolism  in  osteo- 
malacia show  great  disturbances.  Almost  regularly  is  found  negative  calcium 
equilibrium.  Especially  is  the  elimination  of  calcium  through  the  intestine 
increased.  That  therewith  the  phosphorus  is  also  eliminated  in  increased 
amount  in  the  feces  is  not  characteristic  for  osteomalacia,  as  the  calcium 
carries  with  it  the  phosphorus.  The  calcium  contents  of  the  blood  in  os- 
teomalacia is  somewhat  raised  (Capellani).  We  can  see  a  certain  relation 
between  pregnancy  and  osteomalacia  in  that  fact  that  osteophytes  that 
normally  form  during  pregnancy  are  very  poor  in  lime. 

Of  the  hypotheses  that  are  at  hand  as  to  the  pathogenesis  of  osteo- 
malacia, I  mention  those  only  which  concern  the  ductless  glands.  The 
assumption  of  a  specific  thyrogenic  disturbance  cannot  be  accepted  as 
correct,  nor  can  the  view  that  goiter  formation  and  the  osteomalacia  have 
a  causal  connection.  Among  thirty-four  cases  of  osteomalacia,  Bossi  saw  not 
one  with  a  goiter;  and  I  can  also  very  well  reject  the  supposition  of  a  pri- 
mary functional  disturbance  of  the  chromaffin  tissue.     The  sexual  glandular 


OSTEOMALACIA  437 

hypothesis  has  attracted  the  most  adherents.  Through  the  favorable  re- 
sults of  castration,  Fehling  was  furnished  the  occasion  for  regarding  the  cause 
of  osteomalacia  as  a  hyperfunction  of  the  ovaries.  Cristofoletti  modified  this 
hypothesis  by  assuming  that  the  internal  secretory  function  of  the  ovary 
lasts  during  pregnancy,  and  that  this  leads  to  a  hypofunction  of  the  chrom- 
affin tissue. 

For  an  especially  functional  disturbance  of  the  interstitial  glands  speaks 
the  finding  of  Wallart  that  the  interstitial  substance  in  osteomalacia  is 
especially  strongly  developed.  The  assertion  of  Siegert  and  M.  B.  Schmidt 
that  infantihsm  and  osteomalacia  belong  together  is  made  scarcely  plausible 
by  this  fact  alone.  As,  however,  also  in  normal  pregnancy  the  interstitial 
glands  are  more  strongly  .developed,  it  is  questionable  whether  we  may 
estimate  the  value  of  the  findings  of  Wallart  as  high,  although  I  am  unable 
to  bring  anything  else  against  them. 

I  would  not  ascribe  the  hypofunction  of  the  chromaffin  tissue  so  great 
a  value  as  does  Cristofoletti.  As  signs  of  it,  Cristofoletti  quotes:  the  hyper- 
eosinophilia,  the  absence  of  the  adrenalin  glycosuria  and  the  eventually 
present  pigmentations.  But  why,  then,  do  we  never  find  osteomalacic 
manifestations  in  Addison's  disease?  The  combination  of  hypofunction 
of  the  chromaffin  tissue  with  pregnancy  can  not  be  such  an  important  factor, 
for  there  are  cases  of  osteomalacia  without  pregnancy.  Moreover  the 
relations  of  the  chromaffin  tissue  to  the  calcium  metabolism  are  still  rather 
questionable. 

To  my  knowledge,  there  are  no  existing  observations  as  to  whether 
there  is  in  pregnancy  a  continuation  of  ovulation.  After  all,  the  assump- 
tion of  a  hyperfunction  of  the  ovaries  is  up  to  the  present  the  only  one  that 
can  be  supported  by  numerous  and  good  observations.  It  is  at  all  events 
surprising  that  the  osteomalacic  process  is  as  well  influenced  by  both  cas- 
tration and  by  normal  or  artificially  induced  labor.  We  may,  however, 
suppose  with  Halban  that  the  activity  of  the  ovary  and  that  of  the  chorionic 
epithelium  become  summated,  and  that  it  is  therefore  sufficient  to  Hmit 
only  one  of  these  factors.  Also  the  hyperplasia  of  the  parathyroids  perhaps 
is  explained  by  this  hypothesis.  Already  during  normal  pregnancy  are 
greater  demands  made  on  the  parathyroid  glands,  still  greater  demands  may 
lead  to  hyperplasia  (confer  the  chapter  on  the  parathyroid  glands). 

The  observations  of  FdL  that  extracts  of  the  anterior  lobe  of  the  hypo- 
physis influence  osteomalacia  favorably,  turn  our  attention  to  the  hypophysis. 
Perhaps  in  osteomalacia  the  normal  hyperplasia  of  the  anterior  lobe  during 
pregnancy  fails  to  take  place.  Up  to  the  present,  all  these  theories  are  hy- 
potheses, as  between  the  described  and  the  supposed  alterations  in  the  func- 
tion of  the  ductless  glands  and  the  profound  disturbance  in  the  osseous 
system  there  is  still  a  very  wide  gap. 

In  a  thorough  monographic  dissertation  on  osteomalacia  and  rachitis, 


438  THE    DISEASES    OF    THE    SEXUAL    GLANDS 

G.  Pommer  has  upheld  the  view  that  both  diseases  depend  on  an  affection 
of  the  central  nervous  system.  Considering  the  intimate  relationship 
between  the  central  nervous  system  and  the  function  of  the  ductless  glands 
this  supposition  seems  to  me  to  deserve  more  attention  than  it  has  thus 
far  found. 

Addendum 

Whitehead  reports  the  histological  examination  on  the  testicle  of  the 
case  of  E.  M.  Prince.  As  Princess  case  is  very  interesting  and  apparently 
forms  the  only  case  on  record  of  true  human  her.maphroditism  in  which  the 
organs  of  both  sexes  were  present,  it  will  be  quoted  in  extenso: 

The  patient,  apparently  a  girl,  eighteen  years  of  age,  consulted  Prince 
stating  that  she  had  never  menstruated,  and  that  she  suffered  from  headaches 
supposed  to  be  due  to  that  fact;  she  had  withdrawn  from  the  college  she  had 
been  attending  because  of  the  headaches  which  were  worse  about  every 
twenty-eight  days.  She  appeared  to  be  a  healthy,  robust  girl,  refined 
and  intelligent.  There  was  a  heavy  growth  of  hair  upon  the  head,  the 
voice  was  soft  and  feminine  and  the  breasts  well  developed,  rather  larger  than 
ordinarily  seen  in  a  girl  of  her  age.  The  hips  were  typically  feminine,  the 
mons  Veneris  was  rather  scantily  covered  with  hair,  the  labia  majora  were 
normal;  the  clitoris  was  not  enlarged  and  the  hymen  was  unruptured.  No 
uterus  could  be  made  out  by  rectal  examination.  The  vagina  was  about  2  in. 
long,  and  terminated  in  a  blind  pouch.  In  the  upper  part  of  each  labium 
majus  a  body  could  be  felt  which  was  freely  movable.  The  diagnosis  made 
was  congenital  abscess  of  the  uterus  with  hernia  of  both  ovaries.  At  the 
operation  (exploratory  laparotomy)  a  small  body  the  size  of  a  pecan  nut  was 
found  at  the  usual  site  of  the  uterus,  and  to  the  left  of  this  there  was  found  an 
apparently  normal  ovary  with  a  rudimentary  tube.  At  a  subsequent  opera- 
tion the  two  bodies  in  the  labia  majora  were  removed  and  were  found  to  be 
testes,  a  diagnosis  which  was  afterward  confirmed  by  a  pathologist. 

In  this  case  the  secondary  sexual  characters  were  of  the  female  type. 
A  weak  point  in  the  case  is  the  absence  of  the  microscopical  examination  of 
the  bodies  believed  to  be  ovaries. 

Saenger  reports  seven  cases  of  eunuchoidism  which  had  come  under  his 
personal  observation,  and  concludes  that  the  condition  is  by  no  means  so 
rare  as  is  generally  supposed.  His  last  case  is  especially  interesting  in  that 
the  subject  was  an  kyphoscoliotic  acromegalic  individual  aged  thirty-three 
years,  who  developed  a  late  eunuchoidism  in  consequence  of  a  gangrene  of 
the  testicle;  after  the  injury  there  was  a  failure  of  potency,  a  falling-out  of 
the  hairs  of  the  beard  and  pubic  regions — and  in  part  also  of  the  eyebrows 
— but  there  was  no  eunuchoidal  distribution  of  fat,  nor  gigantism. 

All  references  to  the  subject  of  the  sexual  glands  would  be  incomplete 
without  mention  of  the  name  of  Leo  Loeb,  whose  researches  on  the  function 


ADDENDUM  439 

of  the  corpus  luteum  are  epoch-making.  According  to  Loeh  the  corpus 
luteum  suppHes  to  the  uterus  a  sensitizing  substance  which  prepares  it  to 
respond  with  the  production  of  the  maternal  placenta,  if  there  is  added  an 
external  stimulus  of  a  mechanical  nature. 

Seitz,  Wintz,  and  Fingerhut  have  been  able  to  isolate  from  the  cow's 
corpus  luteum  two  bodies.  One  of  these,  a  luteoproteid,  has  hemorrhage- 
checking  properties;  the  other,  a  lecithin  albumin,  has,  in  animals,  a  stimu- 
lating influence  on  the  genitalia.  When  injected  subcutaneously  in  amenor- 
rheic  women,  it  brought  about  menstruation. 

The  knowledge  of  the  relation  of  possible  sexual  glandular  diseases  to 
dementia  precox,  as  suggested  by  positive  Abderhalden  reactions  when  ex- 
tracts of  the  sexual  glands  are  tested  against  the  sera  of  dementia  precox 
patients  is  as  yet  very  obscure.  The  results  of  such  tests  against  the  sera 
of  chlorosis  patients,  would,  in  view  of  the  author's  views  on  the  cause  of 
chlorosis,  be  very  interesting. 

Whitehead  (R.  H.).  The  structure  of  a  testis  from  a  case  of  human  hermaphroditism. 
Anat.  Record,  Vol.  VII,  1913,  p.  St,. 

Saenger  (A.).  Ueber  Eunuchoidismus.  Deutsche  Zeitschrift  fiir  Nervenheilkunde, 
Vol.  LI,  H.  3-6,  1914,  pp.  178-197. 

Loeb  (L.).  The  experimental  production  of  the  maternal  placenta  and  the  function  of 
the  corpus  luteum.     J.  Am.  M.  Assn.,  Oct.  30,  1909,  Vol.  LIII,  No.  18. 

Seitz  (L.),  Wintz  (H.),  and  Fingerhut  (L.).  Ueber  die  biologische  Funktion  des 
Corpus  luteum,  seine  chemischen  Bestandteile,  und  deren  therapeutische  Verwendung 
bei  Unregelmassigkeiten-  der  Menstruation.  Miinchen.  med.  Wchnschr.,  1914,  LV. 
pp.  1657-1661,  1734-1738. 


CHAPTER  XI 

PLURIGLANDULAR  DISEASES 

Multiple  Ductless  Glandular  Sclerosis. — Gigantism 

Already  in  the  first  chapter  we  pointed  out  how  that  in  recent  time 
there  has  been  a  growing  tendency  especially  in  the  French  literature  to 
regard  individual  diseases  of  the  ductless  glands  as  pluriglandular  diseases. 
The  number  of  contributions  as  to  pluriglandular  disease  has  shown  a  steady 
growth.  I  have  already  stated  my  opinion  that  I  regard  this  tendency  as 
mistaken.  It  must  have  the  result  that  the  individual  typical  disease  pic- 
tures will  become  more  and  more  confused  and  that  the  laborious  acquisitions 
[to  our  knowledge]  will  again  become  lost  in  the  general  chaos.  In  order  to 
make  manifest  my  viewpoint  on  this  question,  I  would  again  briefly  capitu- 
late what  I  have  already  stated  in  detail  in  the  first  chapter  as  to  the  physio- 
logical and  pathological  correlations.  The  disease  of  an  individual  duct- 
less gland  regularly  has  as  a  sequel  disturbance  in  the  other  ductless  glands, 
that  eventually  may  be  recovered  from  if  the  gland  primarily  afTected  be- 
comes healthy  or  if.  for  example,  its  absence  of  function  [Ausfall]  has  been 
made  good  by  therapy  (physiological  correlations).  By  pathological  cor- 
relation I  mean  the  phenomenon  that  the  disease  that  has  first  involved  one 
gland  involves,  in  its  further  course,  other  members  of  the  ductless  glandular 
system.  In  the  majority  of  cases,  it  may  readily  be  seen  what  ductless  gland 
was  first  involved;  for  the  most  part  indeed  the  disease  of  that  ductless 
gland  stands  so  much  to  the  fore,  that  in  this  case  also  I  would  rather  avoid 
the  designation  pluriglandular  disease.  Much  more  do  I  consider  it  cor- 
rect to  reserve  this  term  for  those  cases  in  which  the  clinical  picture  shows 
that  the  disease  process  embraces  the  whole  ductless  glandular  system  or  at 
least  a  large  part  of  it.  Multiple  ductless  glandular  sclerosis  must  he  des- 
ignated as  such  a  pluriglandular  ajffection  kot'  lioxw.  In  such  cases  we  have 
to  deal  with  general  symptoms  of  deficiency  [of  function,  Ausfallerschein- 
ungen]  on  the  part  of  the  system  of  ductless  glands. 

The  question  as  to  whether  the  antitype  exists,  that  is,  if  there  occurs  a 
generalized  hyperplasia  of  the  ductless  glandular  system  with  corresponding 
manifestations  of  increased  function,  seems  to  me  not  yet  ripe  for  discussion. 
There  is  no  doubt  that  hyperplastic  changes  in  the  thyroid  gland  and  in  the 
suprarenal  cortex  are  not  rarely  a  concomitant  of  acromegaly.  But  in 
this  case  there  is  no  occasion  to  doubt  the  diagnosis  acromegaly  on  this 
account.     So  much  is  the  picture  dominated  by  symptoms  on  the  part 

440 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  44I 

of  the  hypophysis.  The  only  disease  that  perhaps  belongs  here  is  gigantism. 
Later  I  shall  expound  in  detail  that  I  cannot  regard  gigantism  as  simply  an 
acromegaly  of  child-life,  as  Laiinois  and  Roy  assert.  The  enormously  in- 
creased tendency  to  growth  of  the  entire  body  seems  to  signify  to  me  much 
more  a  rendering  potent  of  the  entire  ductless  glandular  system,  that  is  mostly 
followed  by  a  rapid  exhaustion,  in  which  some  glands,  as  for  example  the 
sexual  glands,  even  at  the  beginning  of  the  disease,  show  signs  of  a  decay 
[of  function]  or  of  a  remaining  backward  in  development.  One  aspect  of 
the  problem  seems  to  me  not  as  yet  explained,  namely,  whether  we  are 
justified  in  regarding  the  potentizing  of  the  ductless  glandular  system  as 
alone  the  cause  of  the  increased  tendency  to  growth  or  whether  we  must  not 
assume  that  from  the  beginning  there  was  an  abnormal  tendency  [mapping- 
out,  i\nlage]  of  the  entire  organism,  including  the  ductless  glands.  It 
seems  to  me,  however,  that  the  inclusion  of  gigantism  among  the  pluri- 
glandular diseases  seems  best  adapted  for  our  purpose. 

Multiple  Ductless  Glandular  Sclerosis 

HHstorical. — A  number  of  the  cases  that  I  shall  group  under  this  term 
appear  in  the  literature  under  very  diverse  designations.  In  the  descrip- 
tion of  late  eunuchoidism  it  was  mentioned  that  the  cases  of  multiple  ductless 
glandular  sclerosis  all  are  associated  with  more  or  less  distinct  symptoms  of 
late  eunuchoidism,  that  however  these  symptoms  constitute  only  a  partial 
manifestation  of  the  picture,  far  richer  in  symptoms,  of  multiple  ductless 
glandular  sclerosis.  A  uniform  conception  of  this  disease  picture  has  not 
as  3'et  permeated  the  French  literature.  Gaudy  describes  as  infantilism 
reversif  ou  tardif  a  part  of  the  cases  here  set  forth  by  myself  and  ascribes  an 
important  etiological  factor  to  a  disease  of  the  thyroid  gland.  Cordier  and 
Rebattu  place  the  sexual  glands  as  the  central  figure  of  the  pathogenesis  and 
distinguish  between  dysorchidie  and  dysorchidie-dysthyroidie.  The  works 
of  Claude  and  Ganger ot  mark  an  essential  advance,  these  authors  in  1907 
having  described  this  clinical  picture  under  the  terms  insuifisance  pluri- 
glandulaire  endocrinienne.  To  my  mind,  however,  Claude  and  Gougerot 
have  lately  gone  too  far,  in  that  they  had  especially  also  later  French  authors 
have  included  under  this  designation  cases  whose  position  [thereunder]  have 
seemed  to  me  uncertain.  I  have  already  dealt  with  this  in  detail  in  the  first 
chapter.  There  I  have  classified  together  under  the  term  multiple  ductless 
glandular  sclerosis  those  cases  in  which  a  primary  simultaneous  disease,  or 
almost  simultaneous  disease,  of  several  glands  exist,  cases  that  we  must  re- 
gard as  correlated  to  the  inflammatory  sclerosis  and  atrophy  of  the  ductless 
glands  as  found  at  autopsy. 

There  are,  of  course,  cases  of  spontaneous  myxedema  or  of  Addison's  dis- 
ease that  likewise  depend  on  inflammatory  sclerosis  of  the  ductless  gland  con- 


442  PLURIGLANDULAR    DISEASES 

cerned.  ^Mostly,  however,  we  are  in  a  position  sharply  to  differentiate  the 
disease  pictures.  In  the  cases  about  to  be  described  we  are  dealing  with  a 
symptom-complex  that  already  in  vivo  suffices  to  let  us  refer  the  diagnosis 
to  a  more  or  less  generalized  sclerosis  of  the  ductless  glands  and  justifies 
us  in  picking  out  this  disease-form  as  an  entity. 

Dejfinition. — As  multiple  ductless  glandular  sclerosis  I  term  that  clinical 
picture  wJiich  is  brought  about  by  a  probably  infectious,  for  the  fnost  part  not 
as  yet  more  well-defined,  disease  process — a  disease  process  that  involves  several 
ductless  glands  simultaneously,  and  leads  to  high-grade  sclerotic  atrophy  and 
hence  to  manifestations  of  deficiency  on  the  part  of  these  glands.  Thyroid  gland, 
sexual  glands,  hypophysis,  and  suprarenals  are  mostly  involved.  Correspond- 
ingly are  found  more  or  less  pronounced  the  manifestations  of  hypothyrosis.  of 
late  eunuchoidism,  and  hypophysial  insufficiency,  combined  with  a  syndrome 
similar  to  Addison's  disease  {hypotonia,  pigmentations,  etc.).  Especially 
brought  info  prominence  is  a  progressive  [i.e.,  uncontrollable]  cachexia,  that 
develops  to  a  high  grade. 

Case  Histories. — Of  the  cases  reported  in  the  literature  I  regard  the  fol- 
lowing as  belonging  to  multiple  ductless  glandular  sclerosis.  At  all  events 
I  must  mention  that  some  of  these  cases  are  not  exactly  enough  described, 
so  that  their  membership  in  the  group  is  not  cjuite  certain. 

Observation  oj  Rumpel. — Man,  thirty-six  years  old.  Great  weakness,  backs  of  hands 
and  feet  thick  and  puffy,  pronounced  cachexia,  and  considerable  anemia,  skin  dry,  weak- 
ness of  memory,  frequent  chills,  temperature  abnormally  low,  penis  of  normal  size,  scrotum 
very  small,  testicles  much  atrophied,  but  still  sensitive.  Cremasteric  reflex  weakened, 
libido  absent.  Scanty  axillary  and  pubic  hair;  also  the  hair  of  the  head  is  thinned  out; 
subcutaneous  fat-tissue  increased,  especially  on  mens  Veneris;  polyuria  and  polydipsia; 
gonorrhea  at  the  age  of  twenty-four  years.  Beginning  of  the  disease  in  the  thirtieth 
year  of  life  with  gradual  loss  of  the  sexual  instinct,  with  thickening  of  the  skin  of  the  dorsa 
of  the  hands  and  feet,  lessening  of  memory,  falling  out  of  hair,  etc.  Thyroid  treatment 
without  result.     No  autopsy. 

Observation  of  Ponfick. — Man,  forty-seven  years  old,  cobbler,  married  since  twenty-third 
year  of  life,  has  six  children.  Since  the  thirty-second  year  has  had  a  gradually-increasing 
fullness  of  the  face,  working  ability  decreased,  the  cheeks  become  puffy,  the  lips  swollen, 
the  skin  rigid  and  pale  as  wax,  the  hair  of  the  head  thinned  out,  the  hair  on  the  cheeks  is 
entirely  absent.  Also  the  mustache  is  thinned  out.  Mimicry  slow,  speech  scanning, 
hearing  diminished,  skin  slightly  colored  cyanotic,  scaly,  the  hairiness  of  the  trunk  and 
extremities  has  decreased  markedly,  the  genitalia  are  almost  entirely  devoid  of  hair. 
Hemoglobin  55  per  cent.  Essential  improvement  on  thyroid  medication,  gain  of  weight, 
8  kg.,  hemoglobin  rises  again  to  75  per  cent.  In  spite  of  continuation  of  the  thyroidin 
treatment,  later  much  puffiness  of  the  face,  diarrheas,  hemoglobin  again  falls,  hearing  be- 
comes worse  (sclerosis  of  the  middle  ear),  body  weight  sinks  lower,  although  thyroidin  is 
no  longer  given.  Death  from  pneumonia.  Thyroid  10.2  gm.,  therefore  only  a  third  of  the 
normal  weight.  The  isthmus  and  the  parts  bordering  on  it  well  retained,  however,  and 
show  tissue  that  is  entirely  capable  of  functionating.  Periarteritis  hemorrhagica. 
Suprarenals  generally  thinned,  cortex  somewhat  smaller.  Hypophysis:  in  the  sella 
turcica  a  large  cavity,  the  posterior  lobe  well  retained,  the  peduncles  of  the  hypophysis 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  443 

penetrate  the  cavity  (hydrops  ex  vacuo),  dura  grown  fast  to  the  underlying  tissue. 
Destruction  of  the  glandular  lobe.  Callous  thickening  in  the  retained  part.  Rigidity  of 
the  fiber  masses. 

Observation  ofGouiUoud. — Woman,  thirty-seven  3'ears  old,  mother  of  three  children,  se- 
vere hemoptysis  at  the  thirty-third  year,  at  that  time  cessation  of  menses,  which  have 
never  been  right  since  that  time;  the  temperament,  which  was  formerly  very  Hvely,  has 
altered,  the  patient  is  apathetic,  forgetful,  childish  mentally.  Cachexia  for  the  last  half 
year.  Face  pale.  Lashes  have  in  part  fallen  out.  .\lso  the  hair  of  the  head  is  thinned 
out  and  has  lost  its  color.  Also  the  hairs  of  the  axilla  and  on  the  pubis  have  fallen  out. 
The  hands  are  cold,  backs  of  the  hands  edematous.  The  thyroid  is  apparently  smaller 
than  normal,  the  uterus  entirely  atrophic.     Improvement  by  thyroid  therapy  doubtful. 

Observation  of  Djemil  Pascha. — ]Man.  eighteen  3^ears  old,  testicles  began  to  atrophy 
three  years  ago,  the  potency  became  lost.  The  mamillae  began  to  increase  in  volume,  also 
the  breasts  became  larger,  the  pitch  of  the  voice  was  higher.  After  operative  removal  of 
the  breasts  libido  returned,  the  testicles  became  larger  again,  pollutions  occurred;  later, 
increasing  paleness  and  puffiness  of  the  skin  of  the  entire  body,  apathy,  increasing  cachexia, 
dryness  of  the  hair.     Aledication  with  thyroidin  unsuccessful,  death,  no  autopsy. 

Observation  of  Claude  and  Gougerot. — Man,  forty-seven  years  old,  formerly  very  potent, 
father  of  three  children,  alcoholism.  At  forty-two  years,  probably  tetany,  also  perhaps 
nephritis.  During  convalescence  falling  out  of  the  hair  of  the  head,  the  testicles  atrophied, 
complete  impotence,  the  voice  altered,  and  also  the  external  genitalia  became  atrophic. 
Hairs  of  the  beard  very  scanty.  Pubic  hair  and  axillarj^  hair  absent.  Skin  drj^,  apathy, 
pigmentations  on  the  skin  and  mucous  membranes,  low  blood-pressure,  asthenia,  gradual 
diminution  in  the  size  of  the  thjToid  gland,  high-grade  cachexia,  tuberculosis  of  the  lungs, 
death.  Autopsy  showed  tuberculous  foci  in  lungs,  liver  and  kidneys.  The  thyroid  very 
small,  only  12  gm.  The  testicles  very  atrophic  (22  gm.),  prostate  and  seminal  vesicles  also 
atrophic.  Hypophysis  smaU  and  sclerotic.  Histological  examination  of  the  skin;  atro- 
phy of  the  epidermis;  hair  follicles,  sweat  glands  and  sebaceous  glands  atrophic. 

Observation  of  Gandy. — Man,  thirty-three  years  old,  formerly  gonorrhea,  father  of  two 
children;  was  very  potent;  at  twenty-seven  3^ears,  polyuria,  headaches,  severe  sweats, 
puffiness  of  the  face,  falling  out  of  hair,  nasal  hj-drorrhea.  Later  retrogression  of  the 
secondary  sexual  characters  and  atrophy  of  the  genitalia.  Looks  like  an  eighteen-year- 
old  youth.  Skin  of  the  face,  pale,  subicteric,  skin  dry,  sHghtly  scaly.  Hairs  of  beard 
very  scanty.  Trunk  and  extremities  bald.  Scrotum  and  testicles  quite  small,  the  latter 
insensitive.  Penis  6-7  cm.  long.  Complete  impotence.  Prostate  also  atrophied.  Cre- 
masteric reflexes  absent.  Perineum  and  genitalia  have  lost  their  pigment.  Autopsy: 
Inflammatory  sclerosis  of  the  th}Toid  (7  gm.),  the  testicles  ver\'  small  (8-10  gm.).  In- 
terstitial substance  has  disappeared  entirely'.  ^leningitic  changes  at  the  base  of  the 
skull,  with  edema  of  the  brain.     Xo  statement  as  to  hj'pophysis. 

Observation  of  Brissaiid  and  Bauer. — Twenty-nine-year-old  woman,  heart  failure,  em- 
boHsm,  tuberculosis,  peritonitis.  First  menses  at  the  age  of  fifteen.  Birth  of  child  at  the 
age  of  twenty.  From  that  time  has  not  menstruated.  Infantile  appearance,  face  very 
pale,  slightly  swollen,  breasts  Httle  developed.  Hair  of  head  dry  and  thinned  out.  likewise 
the  eyebrows,  entire  absence  of  pubic  and  axillary  hair.  Voice  monotonous.  Apathy, 
headaches,  anemia,  and  cachexia.  Autopsy.  Thyroid  15  gm.  apparently  normal.  Xo 
statement  as  to  microscopical  examination.  Left  side  salpingitis  and  oophoritis.  Right 
ovary  much  sclerosed,  verj^  small.  Uterus  like  that  of  a  little  girl.  Xo  statement  as  to 
the  pituitary. 

Observation  of  Sainton  and  Rathery. — Woman,  thirty-two  years  old,  syphilis  at  the  age 
of  twenty-five.  Very  distinct  myxedema,  appears  very  infantile,  absence  of  pubic  and  ax- 
illary hairs.     Hair  of  head  thinned  out,  dry.     Apathy.     Speech  slow,  almost  complete 


444  PLVRIGLAXDULAR    DISEASES 

amaurosis,  pulse  66,  improvement  as  a  result  of  thyroidin  medication.  Autopsy. 
Thyroid  gland  sclerosed,  12  gm.,  thymus  large,  suprarenals  sclerosed.  Genitalia 
atrophic.  Ovaries  very  small,  sclerotic.  Uterus  infantile.  Soft  malignant,  cystic  de- 
generated tumor  of  the  h\-pophysis. 

Observation  oj  Josserand. — ]\Ian,  thirty  j'ears  old,  five  years  ago  influenza  and  articular 
swellings,  later  great  loss  of  body  weight,  marked  weakness,  the  mustache  fell  out,  also  the 
axillary  hair  and  the  eyebrows,  the  skin  of  the  penis  became  thick,  and  inelastic,  atrophy 
of  the  testicles,  loss  of  libido  and  of  potency.  Extreme  weakness,  then  some  improvement. 
Anemia,  senile  appearance.  Testicles  the  size  of  hazelnuts,  bilateral  hemianopsia, 
apparent  increase  in  size  of  the  hands  and  feet. 

Josserand  mentions  in  brief  a  second  case  who  at  the  age  of  thirty-five  passed  safely 
through  an  attack  of  influenza,  and  later  became  senile. 

Observation  of  Gougerot  and  Gy. — IMan,  fifty-two  years  old,  formerly  very  strong,  very 
potent,  at  the  age  of  forty-one  years  a  "hard  to  define"  infectious  disease,  with  pains  in  the 
limbs  and  in  the  abdomen,  vomiting  and  numbness,  lasting  two  and  a  half  months. 
Later  asthenia,  and  temporary'  polyuria.  From  this  time  on  libido  and  potency  gradu- 
ally lessened  and  finally  disappeared.  Hairs  of  the  beard  fell  out.  axillar\'  and  pubic 
hairs  are  almost  entirely  absent.  Senile  appearance,  testicles  atrophied,  sensation  of  cold, 
tuberculosis  of  the  apices,  lupus  on  the  nose,  erysipelas,  later  pneumonia.  Autopsy: 
Thyroid  gland  highly  sclerosed,  right  lobe  6  gm.,  left  lobe  5  gm.  Testicles  likewise 
sclerosed,  right  18  gm.,  left  20  gm.  Suprarenals  sclerosed,  chiefly  in  the  cortex;  pancreas 
also  sclerosed,  likewise  the  hypophysis  (0.3  gm.),  and  the  parathyroids.  Also  liver,  spleen 
and  kidneys  sclerotic. 

Personal  Observation. — Observation  LIII. — Forty-year-old  man  (history  partly  elicited 
from  the  wife  of  the  patient).  Father  of  the  patient  died  at  the  age  of  sixty  years  of 
carcinoma  of  the  stomach,  mother  at  forty-five  j'ears,  of  tuberculosis.  One  brother  also 
died  of  tuberculosis,  otherwise  no  tuberculosis  in  the  family.  One  uncle  died  of  diabetes. 
Xo  gout,  no  obesity,  no  Basedow's,  in  the  family.  The  patient  himself  had  in  his  youth 
passed  through  measles  and  scarlet  fever.  At  twenty  years  of  age,  catarrh  of  the  pul- 
monar>'  apices,  that  became  healed.  The  patient  then  remained  healthy  up  to  his 
thirty-fifth  year.  Sexual  life  was  fully  normal.  He  married  at  the  age  of  twenty-eight 
years  and  has  three  healthy  children.  Hair  of  the  head  abundant,  and  there  was  a  fair 
amount  of  hair  on  the  trunk  and  extremities.  Abundant  beard.  Axillary  and  pubic 
hair  abundant.  Potency  and  libido  entirely  normal.  Had  never  engaged  in  [sexual] 
excesses;  at  the  age  of  twenty-two  years  gonorrhea  and  slight  orchitis.  He  was  never 
especially  strong  muscularly,  was  always  rather  thin,  but  he  felt  well  and  could  always 
fulfill  his  now  and  then  exacting  duties  as  a  tradesman.  At  the  age  of  thirty-five  years 
he  became  ill  rather  acutely  with  fever,  lancinating  pains  in  the  extremities,  pains  in 
the  back  and  neck  (he  cannot  say  whether  the  thyroid  was  swollen).  The  physician 
diagnosed  influenza  and  ordered  aspirin.  For  some  days  later  there  also  existed  diarrhea. 
The  fever  rose  as  high  as  39.5°C.  Later  when  the  acute  manifestations  had  retrograded, 
there  occurred  edema  of  the  legs,  the  face,  and  also  the  backs  of  the  hands  and  feet. 
Albumin  was  found  in  urine  and  the  physician  diagnosed  nephritis.  The  patient  felt 
very  weak,  after  about  eight  weeks  improvement  occurred,  but  the  weakness  persisted; 
convalescence  continued  for  an  unusually  long  time,  for  several  weeks  still  the  patient 
suffered  from  great  muscular  weakness,  he  became  thin,  and  the  edematous  swellings  dis- 
appeared very  slowly.  After  three  months  the  patient  had  recovered,  yet  he  never  felt 
entirely  well  since  that  illness.  The  potency  gradually  became  lost,  and  about  three- 
quarters  of  a  year  after  the  illness  the  testicles  seemed  to  him  to  be  smaller.  Also  the 
penis  was  smaller,  the  hair  of  the  head  had  become  thinned  out  immediately  after  the  ill- 
ness, so  that  some  bald  spots  had  formed,     Xow  also  the  hair  of  the  mustache  and 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  445 

beard  began  to  fall  out,  and  the  axillary  and  pubic  hair  and  the  hair  on  the  trunk  gradu- 
ally disappeared.  Since  this  time  the  patient  has  been  an  invalid.  Later,  the  physicians 
regarded  the  nephritis  as  cured;  although  the  puffiness  of  the  skin  never  left  entirely. 
The  patient  is  very  apathetic,  tires  very  easily,  shivers,  is  never  quite  warm,  has  never 
attained  his  former  body  weight,  mental  work  exerts  him  very  much,  he  sleeps  poorly 
at  night,  suffers  from  pressure  in  the  head,  sometimes  complains  of  drawing  pains  in 
the  back  and  legs;  lately  the  swelling  of  the  face  has  again  become  distinct.  Also  the 
pallor  of  the  face  has  increased.  He  has  visited  different  bath  resorts  and  taken  many 
medicines,  among  them  iodine  and  arsenic.  The  bowel  movements  often  occur  at  inter- 
vals of  four  to  five  days.     Recently,  albumin  has  again  been  found  in  the  urine. 

The  patient  came  under  my  observation  in  May,  191 1.  Medium  height,  cachectic 
appearance,  looks  very  much  older.  Face  pale  with  a  light  yellowish  tinge.  Distinct 
puffiness  of  face,  especially  about  the  eyes,  on  the  cheeks  and  lips.  Light  livid  discolora- 
tion of  the  middle  of  the  cheeks.  On  the  upper  lips  mustache  hairs  very  scanty;  chin 
and  cheeks  bald.  Hair  of  head  thinned  out,  dry,  and  brittle,  at  certain  places  much  more 
scanty,  especially  on  the  occiput.  The  trunk  is  bald,  there  are  no  hairs  in  the  axilla;  at  the 
root  of  the  penis  a  few  scanty  hairs  only,  the  perineum  is  almost  free  from  hair.  Tongue 
perhaps  somewhat  thickened.  Teeth  poor,  partly  carious,  the  crowns  much  worn  away, 
transverse  folds  on  the  forehead,  skin  in  the  supraclavicular  fossae  shows  slight  pad-like 
thickening,  elastic;  also  the  skin  on  the  backs  of  the  hands  and  feet  is  more  elastic,  other- 
wise skin  on  trunk  is  rather  rich  in  fat.  Several  lens-shaped  specks  of  pigment  on  the 
mucous  membrane  of  the  cheeks.  Many  places,  on  the  skin  more  strongly  pigmented  as 
in  the  folds  of  the  palm  of  the  hand,  also  in  the  vicinity  of  the  nipples,  on  the  backs  of  the 
hands,  forearms,  also  about  the  waist.  Breasts  not  enlarged.  Mons  Veneris  rather  rich 
in  fat ;  no  especial  deposition  of  fat  on  hips.  Findings  as  to  cranial  nerves  entirely  normal, 
except  that  Chvostek  II  distinctly  positive.  Trousseau  negative.  Pupils  react  promptly. 
Eye-grounds  normal.  Patellar  reflexes  weak.  Size  of  heart  normal  to  percussion;  faint, 
weak,  systolic  murmur  at  Erb's  point.  Pulse  68,  tension  slight,  blood-pressure  (i?CTa 
Rocci)  65,  liver  not  enlarged,  spleen  not  distinctly  palpable,  neighborhood  of  the  kidneys 
on  each  side  not  especially  sensitive  to  pressure.  Penis  small,  about  7  cm.  long.  Skin  on 
penis  folded.  Testicles  on  each  side  about  the  size  of  a  bean,  soft,  epididymis  also  small, 
somewhat  hardened.  Scrotum  small,  soft.  Examination  per  rectum  shows  that  the 
prostate  is  very  small.  Examination  of  the  blood:  leucocytes  12,000  of  which  51  per  cent, 
are  neutrophiles  and  5  per  cent,  eosinophiles.  In  the  urine  no  sugar,  traces  of  albumin. 
Slight  dulness  over  the  right  apex,  very  few  rales.  Vesicular  murmur  somewhat  weakened. 
Therapy.  Thyroidin  tablets  o.i  gm.  t.i.d.  After  two  and  one-half  months  report 
by  letter  that  the  myxedematous  manifestations  have  improved,  but  the  deteriora- 
tion in  strength  has  progressed. 

Symptomatology. — The  cases  described  show  a  very  noteworthy  agree- 
ment with  one  another.  It  is  therefore  not  difficult  to  delineate  the  clinical 
picture  of  the  condition.  All  cases  show  in  pronounced  manner  the  symp- 
toms of  late  eunuchoidism,  an  exact  description  of  which  I  need  not  enter  into 
here.  This  syndrome,  however,  constitutes  only  one,  although  one  of  the 
most  emphatic  expressions  in  the  total  picture  of  the  disease.  To  it  is 
added  in  all  cases  a  most  irresistibly  progressive  cachexia,  and  mostly  also, 
as  far  as  investigations  have  determined,  a  pronounced  anemia.  Hence  it 
occurs  that  such  patients  in  spite  of  the  boyish  beardlessness  of  face,  do  not, 
as  in  late  eunuchoidism  appear  younger  than  they  really  are,  for  the  most 


446  PLrRIGLAXDULAR    DISEASES 

part  they  rather  appear  prematurely  old.  and  in  some  cases  the  face  has 
even  a  senile  appearance.  There  never  occurs  the  development  of  an  adi- 
posity of  the  type  of  the  eunuchoids.  For  the  most  part  there  rather 
occurs  an  increasing  emaciation,  which  is  associated  with  a  feeling  of  weak- 
ness and  with  chills,  and  which  persists  in  spite  of  all  attempts  at 
feeding  up.  Then  there  occurs  more  or  less  pronounced  puffiness  of  the 
skin  of  the  face,  especially  of  the  cheeks,  and  of  the  skin  of  the  backs  of  the 
hands  and  feet,  in  many  cases  quite  pronounced  myxedema,  which  partially 
but  not  entirely  retrogresses  on  thyroidin  medication.  There  usually  are 
added  to  the  falling  out  of  the  hair  on  the  face,  trunk  and  extremities, 
thinning  out  of  the  hair  of  the  head,  eventually  falling  out  of  the  hairs 
in  spots,  such  as  is  seen  in  true  myxedema,  also  thinning  out  of  the  eye- 
brows, eyelashes,  and  symptoms  that  also  do  not  belong  to  true  late 
eunuchoidism.  Also  brittleness  of  the  nails  was  observed  in  my  case. 
The  loosening  of  the  teeth,  and  especially  the  marked  wearing  down  of 
the  crowns,  as  I  saw  in  my  case,  perhaps  too  belong  to  the  cHnical  picture. 
In  many  cases  are  found  in  addition  to  the  puffiness  of  the  skin,  pronounced 
atrophy  of  the  rest  of  the  skin,  and  marked  dryness  and  exfoliation.  There 
further  develops  in  the  majority  of  cases  pigmentations  of  the  skin,  especially 
in  places  exposed  to  light  or  where  the  clothing  presses,  sometimes,  too,  dis- 
tinct pigmentations  of  the  mucous  membrane  as  in  Addison's  disease;  in 
other  cases  a  pigmentation  that  is  more  brownish  is  noticed.  Almost  in  no 
case  are  absent  asthenia  that  increases  to  high-grade  prostration  of  strength, 
mental  sluggishness  and  apathy,  further  a  feeling  of  pressure  in  the  head, 
forgetfulness.  insomnia,  and  eventually  transitory  rheumatoid  pains  in  the 
limbs.  In  addition  there  exists  hypotonia.  The  sugar  content  of  the  blood 
has  not  as  yet  been  investigated.  In  cases  in  which  the  blood  has  been 
examined  have  been  found  in  addition  to  the  anemia,  slight  leucocytosis  with 
mononucleosis  and  eosinophilia.  Temporary  polyuria  has  been  reported 
remarkably  frequently  (RumpeL  Gaudy.  Gougerot  and  Gy).  Occasionally 
also  occur  tetanic  convulsions  {Claude  and  Gougerot),  or  at  least  the  symptoms 
of  a  latent  tetany. 

The  tracing  of  the  relationship  of  the  numerous  symptoms  to  the  diseases 
of  the  individual  ductless  glands  often  meets,  as  will  be  understood,  with  diffi- 
culties. It  seems  to  me  that  the  simplest  to  explain  is  the  syndrome  that  we 
learned  to  know  in  the  exposition  of  late  eunuchoidism,  and  that  comes  about 
through  the  degeneration  of  the  sexual  glands.  It  should  only  be  mentioned 
in  addition  that  in  the  cases  that  affect  women,  the  retrogression  of  the 
genital  apparatus  and  of  the  secondary  sexual  characters  are  present  in  a  pro- 
nounced manner.  At  all  events  we  cannot  in  the  cases  with  pronounced  retro- 
gression of  the  genital  apparatus,  and  especially  of  the  hair  of  the  mustache, 
exclude  the  possibility  that  a  degeneration  of  the  suprarenal  cortex  does  not 
play  a  role.     In  male  individuals,  it  appears  to  me  only  necessary  to  assume 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  447 

such  an  involvement  of  the  suprarenal  cortex  in  the  crassest  cases,  as  in 
traumatic  late  eunuchoidism,  in  which  the  etiological  factor  is  quite  clear, 
quite  severe  manifestations  of  retrogression  may  occur.  In  women,  however, 
there  may  perhaps  be  ascribed  to  the  suprarenal  cortex  a  greater  signifi- 
cance in  this  direction,  for  we  see  after  castration  very  slightly  pronounced 
the  ordinary  retrogression  of  such  secondary  sexual  characters  as  the  hairi- 
ness of  the  axillae  and  of  the  genitalia. 

The  changes  in  the  hair  of  the  head  are  to  be  referred  to  a  degeneration 
of  the  thyroid  gland,  as  are  also  trophic  disturbances  of  the  nails,  probably 
also  of  the  teeth,  and  further  the  apathy,  headache,  forgetfulness,  etc., 
finally  the  myxedema  of  the  skin.  At  all  events  it  seems  to  me  questionable 
whether  the  myxedematoid  consistence  of  the  skin  is  always  of  purely  thyro- 
genic  origin,  as  thyroidin  medication  very  often  does  not  fully  control  it. 
Such  myxedematoid  alteration  of  the  skin  is  found  not  infrequently  in  the 
hypophysial  dystrophia  adiposo-genitalis;  further  such  alterations  occur  not 
rarely  if  cachexia  develops  in  Basedow's  disease.  I  refer  to  the  chapter 
dealing  with  this  subject,  and  would  like  only  to  express  the  conviction  that 
in  such  cases  the  skin  changes  may  be  brought  into  relationship  with  a 
(even  simultaneous)  degeneration  of  the  glandular  hypophysis. 

The  sclerosis  of  the  hypophysis  may  also  very  well  play  a  part  in  the 
rapidly  progressive  cachexia.  That  there  does  not  ensue  a  distinct  develop- 
ment of  hypophysial  obesity  is  intelligible  when  we  consider  the  general 
cachexia  in  multiple  ductless  glandular  sclerosis.  If  individuals  who  are 
not  yet  fully  developed  were  to  become  the  subjects  of  this  disease,  the 
absence  of  the  eunuchoidal  tall  height  would  also  be  intelligible,  as  the  action 
of  the  insufficiency  of  the  sexual  glands  on  the  development  of  the  skeleton 
might  be  compensated  by  the  insufficiency  of  the  hypophysis.  I  would 
bring  still  another  symptom  into  relation  with  the  hypophysis — the  transi- 
tory polyuria.  As  is  known  we  find  this  symptom  quite  commonly  in 
diseases  of  the  hypophysis,  or  in  pathological  processes  at  the  base  of  the 
skull.  We  may  readily  conceive  that  sclerosing  processes  that  have  be- 
come established  in  the  anterior  lobe  of  the  hypophysis  temporarily  act  as 
irritants  on  the  posterior  lobes  or  on  the  pars  intermedia.  From  this  stand- 
point it  seems  to  me  worthy  of  mention  that  two  of  the  cases  of  late  eunuch- 
oidism reported  in  the  tenth  chapter,  in  which  we  found  transitory  polyuria, 
developed  after  an  acute  infectious  disease  or  after  lues.  Here  the  polyuria 
may  well  be  regarded  as  hypophysial. 

Hypotonia,  high-grade  asthenia  and  the  pigmentations  serve  as  mani- 
festations of  absence  or  deficiency  [Ausfall]  on  the  part  of  the  suprarenals  or, 
much  more,  the  suprarenal  medulla.  Finally  the  tetanic  spasms  that  occur 
point  to  an  involvement  of  the  parathyroid  glands  in  the  disease  process. 
Here  perhaps  it  may  be  thought  that  the  lowering  of  the  thyroidal  and 
suprarenal  activities  can  antagonize  the  occurrence  of  distinct  tetanic  symp- 


448 


PLURIGLAXDULAR    DISEASES 


toms  even  where  there  is  high  insufficiency  of  the  parathyroid  glands.  I 
know  that  much  that  is  h^^jothetical  is  bound  up  with  these  attempts  at 
explanation.  In  one  point,  however.  I  believe  I  can  scarcely  err,  namely,  in 
the  supposition  that  the  rapidly  progressing  cachexia  that  is  observed  so 
frequently  finds  its  explanation  not  in  the  functional  disturbance  of  one 
ductless  gland,  but  in  the  progressive  degeneration  of  the  ductless  glandular 
system. 

The  etiology  of  multiple  ductless  glandular  sclerosis  of  the  ductless  glands 
seems  to  be  of  diverse  nature.     In  manv  of  the  cases  acute  infectious  diseases 


Fig.  77. — Case  with  insufficiency  of  sev- 
eral ductless  glands  (Observation  LIV). 


Fig.  78. — Slightly  myxedematous  facial  expression. 


have  preceded  the  beginning  of  the  disease.  Thus  in  the  case  of  Josserand, 
influenza;  in  the  case  of  Gougerot  and  Gy  a  '"hard  to  define  acute"  illness 
occurred,  as  in  my  case  also.  The  case  of  Sainton  and  Rathery  was  syphilitic. 
In  the  case  of  Claude  and  Gougerot.  and  in  that  of  Brissaud  and  Bauer  there 
existed  at  the  same  time  tuberculosis.  Histologically,  in  the  cases  in  which 
there  were  autopsies,  there  was  found  a  simple  sclerosis;  except  in  the  case 
of  Claude  and  Gougerot^  where  there  was  found  in  addition  tubercle  in  the 
thyroid  gland.  It  is  indeed  very  likely  that  the  ductless  glandular  sclerosis 
may  depend  very  often  on  a  tuberculous  foundation,  as  Poncet  and  Leriche 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  449 

mention,  although  I  cannot  follow  the  connection  of  ideas  of  these  authors 
when  they  ascribe  to  cases  of  dystrophia  adiposo-genitalis,  yes  even  to  cases 
of  acromegaly,  a  tuberculous  foundation. 

In  many  cases  the  disease  picture  of  multiple  ductless  glandular  sclerosis 
develops  quite  spontaneously,  without  a  preceding  or  an  accompanying 
disease.  The  opinion  of  Claude  and  Gougerot  that  there  exists  in  such  cases 
a  congenital  weakness  of  the  ductless  glandular  system,  so  that  a  not  well- 
definable  deleterious  agent  brings  this  system  to  degeneration,  is  not  im- 
probable. In  such  cases  the  organism,  especially  that  which  is  still  in  a  state 
of  development,  may  come  to  a  temporary  manifestation  of  insufhciency 
on  the  part  of  the  ductless  glandular  system. 

I  would  regard  the  following  as  such  a  case: 

Observation  LIV . — J.  K.,  seventeen  years  old  (first  medical  clinic).  One  year  ago 
typical  tetany,  two  months  ago  typical  epileptic  attacks  for  the  first  time.  Now  tetany 
again.  Of  medium  height,  pale  color  of  face,  skin  somewhat  dry  and  exfoliative.  Face 
distinctly  myxedematous,  especially  the  eyelids.  On  the  backs  of  the  hands  slight 
myxedematous  swellings.  Hairs  of  the  beard  and  axillse  are  entirely  absent,  as  is  also  the 
hairiness  of  the  linea  alba  and  the  calves.  Scanty  hairs  at  the  root  of  the  penis.  The 
testicles  are  very  small  and  soft.  As  yet  no  libido,  never  erections  nor  pollutions. 
Finger  nails  very  compact,  strongly  curved,  and  ridged  longitudinally.  Teeth  through- 
out strikingly  small  and  poorly  developed,  terrace-like  striations  on  the  enamel  (whether 
he  had  tetany  in  childhood  cannot  be  elicited).  Ossification  normal.  Blood-pressure  65. 
On  the  administration  of  even  200  gm.  dextrose,  no  glycosuria.  Neutrophile  cells  54  per 
cent.  Typical  tetanic  attacks.  Slight  apathy;  on  thyroidin  medication  the  myxede- 
matous symptoms  disappear  entirely,  the  blood-pressure  soon  rises  to  normal,  the  blood 
picture  becomes  normal. 

After  a  year  the  case  was  examined  by  Redlich.  There  were  new  attacks  of  tetany,  also 
epilepsy.  There  was  nothing  to  be  seen  of  the  myxedematoid  symptoms,  the  second- 
ary sexual  characters  had  for  the  greater  part  developed,  and  the  sexual  life  had  begun 
to  assert  itself. 

Thus  in  this  case  there  existed,  in  addition  to  typical  tetany  and  epilepsy, 
a  simultaneous  disturbance  of  the  function  of  the  thyroid  gland  and  of  the 
sexual  glands.  Perhaps  the  suprarenals  (pronounced  hypotonia)  were  also 
involved.  Probably  the  inhibition  of  development  of  the  sexual  glands 
was  not  occasioned  directly  by  the  disease  of  the  thyroid.  For  this 
speaks  the  fact  that  thyroid-gland  therapy  immediately  brought  the  mani- 
festations of  hypothyroidism  to  disappearance,  while  the  insufficiency  of 
the  sexual  glands  gradually  disappeared  spontaneously. 

Claude  and  Gougerot  believe  that  also  alcoholism  may  furnish  an  etiological 
factor.  In  this  respect  two  cases  of  general  hemochromatosis ,  concerning 
which  Falk  has  reported,  are  of  interest.  As  is  known,  there  are  found  in 
such  cases  pronounced  sclerosis  of  the  liver  and  mostly  also  of  the  pancreas. 
In  both  the  cases,  as  I  myself  had  occasion  to  observe,  there  was  also  a  pre- 
mature diminution  or  cessation  of  the  genital  function,  without  the  history 
29 


45°  PLURIGLANDULAR    DISEASES 

furnishing  a  basis  for  a  preceding  disease  of  the  genitaha.  In  both  cases 
there  was  found  an  almost  complete  falling-out  of  hair  on  the  trunk  and 
the  extremities,  and  also  that  in  the  axillae  and  on  the  pubis.  The  histo- 
logical examination  of  an  excised  piece  of  skin  showed,  in  addition  to  collec- 
tions of  pigmentation,  abundant  connective-tissue  proliferation  of  the  cutis; 
and  in  places  the  sweat-glands  and  the  hair  follicles  were  replaced  by 
connective-tissue  strands.  Falk  believed  that  this  sclerosis  was  also  the 
cause  of  the  falling-out  of  the  hair.  I  incline  more  to  the  supposition  that 
the  involvement  of  the  sexual  glands  in  the  general  sclerosis  had  led  to  a  retro- 
gression of  the  secondary  sexual  characters. 

For  this  assumption  I  find  support  in  the  investigations  of  WeicJiselhaum 
and  Kyrle.  In  individuals,  who  do  not  as  yet  stand  under  the  influence  of 
the  senium,  Weichselhaum  and  Kyrle  found  on  account  of  alcoholism  cirrhotic 
alterations  of  the  testicles,  aft"ecting  interstitial  cells  as  well  as  the  glands  of 
generation. 

In  the  broad  field  of  multiple  ductless  glandular  sclerosis  belongs  perhaps 
a  disease  that  ?.  Xoorden  has  described  as  degeneratio  genito-sclerodermica. 
It  affects  young,  previously  healthy,  girls,  in  whom  after  a  previously  normal 
development  the  menstrual  periods  suddenly  cease  at  the  termination  of  an 
acute  infectious  disease.  There  are  marked  emaciation  and  loss  of  appe- 
tite, a  premature  senility  occurs,  and  there  develop  trophic  disturbances 
of  the  skin ;  in  some  cases  in  which  the  condition  was  looked  for,  the  body 
of  the  uterus  was  found  to  be  atrophic. 

Further  I  would  mention  for  consideration  whether  such  a  multiple  duct- 
less glandular  sclerosis  does  not  exist  in  many  cases  of  pedatrophy.  Thompson 
has  described  a  noteworthy  case  in  which  sclerotic  processes  were  found  in  all 
the  ductless  glands. 

Finally  I  might  here  mention  an  apparently  rather  typical  disease  picture 
of  which  Sir  Jonathan  Hutchinson,  Hastings  Gilford  and  recently  Variot 
and  Pironneau  have  furnished  examples.  Hastings  Gilford  designates  these 
cases  as  "progeria"  Variot  and  Pironneau  as  "nanisim  type  senile."  As  we 
shall  see  directly  much  speaks  against  our  classifying,  without  other  con- 
sideration, these  cases  with  multiple  ductless  glandular  sclerosis.  I  would 
say  here,  however,  that  at  least  an  indirect  connection  with  the  ductless 
glandular  s3-stem  is  here  possible,  and  that  the  inclusion  of  the  condition  at 
another  place  appears  to  me  less  to  the  purpose. 

I  will  here  shortly  report  the  three  cases  described  up  to  the  present.  In  the  case  of 
Hastings  Gilford  the  observation  extended  between  the  fourteenth  and  eighteenth  years 
of  life  of  the  individual  affected.  A  photograph  of  the  individual  taken  at  the  second 
year  of  life  shows  that  the  hair  of  the  head  was  markedly  thinned  out  already  at  that  time; 
at  the  later  investigations  the  patient  showed  a  marked  remaining  behind  in  growth  and  in 
entire  development.  At  fourteen  years  of  age  the  boj'  was  113  cm.  tall,  weighed  16  kg. 
He  was  extremely  thin,  so  that  the  cartilages  of  the  nose  and  the  veins  and  the  tendons  of 
the  entire  body  were  very  prominent.     The  head  was  rather  large,  the  facial  skeleton 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  45 1 

relatively  small.  There  were  on  the  head  only  a  few  thin  hairs,  the  eyebrows  and  the 
lashes  were  absent,  almost  completely,  as  were  also  the  hairs  of  the  trunk.  The  lower  jaw 
was  ill-developed,  and  there  was  especially  a  poor  development  of  the  clavicles.  The  mus- 
culature was  poorly  developed,  the  genitalia  were  about  one  or  two  years  behind  in  their 
development,  the  skin  was  thin  and  dry,  the  nails  were  short  and  the  anterior  fontanelle 
had  not  as  yet  closed,  and  certain  of  the  temporary  teeth  were  still  present.  There  was  a 
falsetto  voice;  the  intelligence  was  rather  well  developed.  The  individual  made  quite  a 
senile  impression.  At  the  age  of  eighteen,  the  boy  died  with  symptoms  that  gave  thought 
to  the  diagnosis  of  "thymic  or  cardiac  asthma."  At  autopsy  was  found  an  enlarged 
thymus  gland  and  atheromatous  alteration  of  the  mitral  and  aortic  valves;  the  coronary 
arteries  were  highly  sclerotic.  The  capsule  of  the  spleen  was  thickened,  the  kidneys  were 
fibrous,  the  walls  of  the  intestines  and  stomach  were  so  atrophied  that  they  were  almost 
transparent.  The  liver  was  relatively  large,  the  brain  normal.  The  long  tubular  bones 
were  rather  slender,  but  the  ends  much  thickened.  Especially  the  condyles  of  the  femurs 
and  the  arterial  ends  of  the  clavicles  were  swollen  up.  Ossification  had  been  premature. 
Microscopically  the  ductless  glands  (thyroid,  hypophysis,  testicles  and  suprarenals)  were 
apparently  normal,  there  was  no  microscopical  examination. 

Hutchinson  observed  a  three-and-a-half-year-old-boy  with  the  same  disease.  Hastings 
Gilford  saw  this  case  when  it  was  fifteen  years  of  age  and  followed  it  to  its  death  two  years 
later.  There  existed  extreme  emaciation,  so  that  the  bones  and  the  tendons  were  very 
prominent.  The  abdomen  was  large,  the  condyles  of  the  tubular  bones  were  rather  thick- 
ened, especially  the  distal  epiphyses  of  the  femurs,  so  that  the  patellas  were  pushed 
forward.  The  fingers  were  short,  the  size  of  the  hands  corresponding  to  that  of  a  three- 
year-old  child.  The  ossification  represented  that  of  a  twenty-year-old  youth.  There 
were  symptoms  of  a  mitral  and  aortic  failure,  and  death  occurred  with  symptoms  of  a 
cardiac  syncope.     There  was  no  autopsy. 

.  The  case  of  Variot  and  Pironneau  was  that  of  a  fifteen-year-old  girl.  She  weighed  only 
11.65  kg. — like  a  two-year-old  child — was  102  cm.  in  height,  size  and  dimensions  corre- 
sponding with  those  of  a  five-year-old  child.  The  appearance  was  entirely  senile.  Apart 
from  isolated  hairs  on  the  head,  the  hair  was  entirely  absent,  even  the  hairs  of  the  eyebrows 
and  lashes.  The  skin  was  thin  and  folded,  the  panninculus  adiposus  was  entirely  absent. 
The  muscles  were  relatively  well  developed,  and  stood  up  prominently  through  the  thin 
skin.  The  nails  were  very  small,  the  tooth  formation  was  very  bad,  and  second  dentition 
was  just  appearing.  Many  teeth  have  fallen  out  without  especial  pain.  The  develop- 
ment of  the  genitalia  had  remained  behind,  and  breasts  especially  had  not  developed. 
The  intelligence  was  rather  good.  Up  to  the  fifteenth  month  development  had  been  en- 
tirely normal,  and  from  this  time  it  had  remained  behind.  X-ray  examination  showed 
that  the  lower  jaw  was  very  atrophic  and  that  the  epiphysial  junctures  had  for  the  most 
part  closed.  Gilford  Hastings  reports  also  a  case  of  Ransom  that  possibly  belongs  here. 
It  was  concerned  with  a  twenty-seven-year-old  girl  who  was  135  cm.  tall  and  weighed  16 
kg.  The  father  had  been  a  heavy  alcoholic.  The  girl's  intelligence  was  feebly  developed. 
Diarrhea  had  existed  from  youth,  and  later  there  had  been  a  diabetes.  The  genitalia  in 
their  development  represented  those  of  a  ten-year-old  girl.  The  ovaries  were  absent. 
The  girl  was  markedly  emaciated  and  looked  pronouncedly  senile.  At  autopsy  there  were 
found  fibrous  changes  in  the  spleen,  lymph  glands,  the  pancreas,  kidneys,  suprarenals, 
thyroid,  hypophysis,  etc.  The  heart  weighed  6  oz.  (about  176  gm.)  and  there  were  athero- 
matous changes  in  the  aortic  and  mitral  valves  and  in  the  aorta. 

The  cases  cited  show  the  greatest  similarity  to  one  another.     Already 
Hastings  Gilford  remarked  that  his  case  and  that  of  Hutchinson  were  so  similar 


452  PLI'RIGLAXDrLAR    DISEASES 

that  the  father  of  the  tirst  when  shown  the  photograph  of  the  second  beUeved 
momentarily  that  it  was  that  of  his  child.  Also  the  case  of  Variot  and  Piron- 
neau  was  similar  to  the  tirst  two,  as  is  seen  in  the  photographs  these  authors 
publish;  it  is  also  remarked  by  them,  although  their  case  is  that  of  a  girl. 
In  all  cases  the  disturbance  in  development  began  in  the  earliest  youth.  In 
all  the  inhibition  of  growth  was  very  considerable,  so  that  we  could  really 
speak  of  dwarfism.  In  all  there  was  extreme  emaciation,  with  the  skin  thin 
folded.  In  all  were  the  muscles  rather  prominent.  The  osseous  s\'stem 
showed  the  characteristic  alterations.  The  dimensions  remained  childlike. 
The  lower  jaw  was  rather  poorly  developed,  apparently  also  the  upper  jaw, 
causing  perhaps  the  aquiline  nose  observed  in  all.  The  long  bones  were 
relativelv  slender,  the  ends  of  the  bones  thickened,  the  closure  of  the  epiphyses 
was  rather  premature.  The  genitalia  remained  backward  in  development  in 
all  cases;  and  finally  the  absence  of  hair  is  common  to  all,  affecting  not 
only  the  hairiness  belonging  to  the  so-called  secondar}'  sexual  characters, 
that  on  the  lip,  chin,  axillae,  pubis,  and  trunk,  but  also  the  hair  on  the  head, 
lashes,  and  eyebrows.  This  increased  the  senile  appearance,  which  in  all 
these  cases  is  of  high  degree. 

That  here  we  are  dealing  with  a  morbid  entity  can  in  all  likelihood  be  as- 
sumed from  the  similarity  of  the  cases  and  the  course  of  the  disease.  On  the 
contrary  the  pathogenesis  of  this  condition  and  the  role  of  the  ductless 
glandular  system  in  the  same  seem  to  me  to  be  as  yet  but  little  clear.  Variot 
and  Pironneau  point  out  that  in  the  case  of  Hastings  Gilford  the  suprarenal 
showed  fibrous  degeneration,  and  see  in  the  disease  picture  the  sequel  of  a 
suprarenal  insufficiency's  setting-in  in  youth.  A  pert  goes  still  further 
and  sees  the  cause  in  a  damaging  of  the  suprarenal  cortex.  On  account 
of  the  characteristic  disturbances  in  the  hairiness  and  in  the  genital  sphere 
he  sees  in  this  disease  a  countertype  to  that  of  tumors  of  the  suprarenal 
cortex.  Hastings  Gilford  believes  on  the  contrary  that  we  are  to  ascribe 
to  the  h^^pophysis  a  "growth  center"  of  considerable  importance.  The 
results  of  the  one  autopsy  done  on  these  cases  up  to  the  present  are  insufficient, 
as  there  was  no  microscopical  examination  of  the  ductless  glands.  It  was 
mentioned  only  that  the  suprarenals  were  sclerosed.  In  the  case  of  Ransom, 
that  does  not  belong  with  certainty  to  this  group,  the  other  ductless  glands 
were  also  apparently  sclerosed.  If  now  also  the  microscopical  examination 
in  such  cases  would  also  furnish  an  extensive  sclerosis  of  the  several  ductless 
glands,  it  would  not  necessarily  be  shown  the  disease  of  the  ductless  glands 
was  primary;  it  would  also  be  possible  that  we  might  be  dealing  with  a  dift'use 
sclerotic  process  involving  the  entire  body,  that  has  also  involved  the  ductless 
glandular  system,  such  a  general  process  as  we  regarded  above  as  possible 
for  hemochromatosis  and  which  is  perhaps  also  true  for  pedatrophy. 

Then  we  would  be  dealing  with  a  secondary  sclerosis  of  the  ductless 
glandular  system,  that  at  all  events  lends  to  progeria  man}^  of  the  striking 


MULTIPLE    DUCTLESS    GLANDULAR    SCLEROSIS  453 

features  of  ductless  glandular  sclerosis,  and  which  may  play  the  chief  role 
in  the  enormous  cachexia  and  the  senilism  of  these  individuals. 

In  the  clinical  picture  of  progeria  are  some  features  that  seem  to  me 
hardly  compatible  with  the  assumption  of  a  ductless  glandular  sclerosis. 
In  the  three  typical  cases  the  intelligence  was  fairly  well  developed,  which 
rules  out  a  strong  involvement  of  the  thyroid  gland.  Especially,  however, 
does  it  seem  to  me  that  the  premature  ossification  points  to  a  sclerosing 
process  independent  of  the  ductless  glandular  system,  as  otherwise  we  would 
expect  considerable  retardation  of  ossification.  The  severe  disturbance  in 
the  development,  or  the  retrogression  of  the  hair,  can  indeed  very  well  be 
brought  into  relation  with  an  involvement  of  the  suprarenal  cortex;  it  is, 
however,  conceivable  that  it  has  its  foundation  in  a  severe  atrophy  of  the 
skin.  It  was  already  in  the  first  chapter  pointed  out  that  we  must  not  re- 
gard old  age,  as  Lor  and  does,  simply  as  a  gradual  degeneration  of  the  ductless 
glandular  system;  but  consider  that  the  ductless  glandular  system,  like 
the  rest  of  the  organs  takes  part  in  a  general  involution  of  old  age.  It 
seems  to  me  that  the  same  thought  can  be  applied  also  to  premature  and 
to  childish  senility. 

Differential  Diagnosis  of  Multiple  Ductless  Glandular  Sclerosis. — The 
cases  out  of  the  literature  that  I  have  quoted  show  a  remarkable  agreement 
with  each  other,  so  that  for  the  most  part  the  diagnosis  does  not  meet  with 
difi&culty,  especially  so  in  that  the  retrograde  processes  in  the  genitalia  and 
the  secondary  sexual  characters  constitute  especially  striking  symptoms. 
The  delimitation  from  pure  late  eunuchoidism  may  indeed  become  difficult. 
Marked  pufiiness  of  the  skin,  thinning  of  the  hair  of  the  head  in  patches, 
and  of  the  hair  of  the  lashes  and  eyebrows,  speak  against  late  pure  eunuch- 
oidism, as  do  also  marked  emaciation  and  cachexia.  For  the  dehmita- 
tion  from  pure  myxedema  I  regard  as  important  the  partial  or  extremely 
deficient  results  attending  thyroid-gland  therapy.  Concerning  the  diagnosis 
from  pure  Addison's  disease  nothing  further  need  be  said.  As  far  as  diag- 
nosing it  from  hypophysial  dystrophia  adiposo-genitalis  is  concerned,  I 
do  not  known  that  in  this  disease  such  a  high-grade  atrophy  of  the  genitalia 
of  adults  occurs  as  was  described  under  late  eunuchoidism;  naturally  the 
absence  of  symptoms  of  brain  tumor  is  also  important,  although  it  must 
be  remembered  that  in  the  case  of  Sainton  and  Rathery  there  was  found  at  the 
same  time  a  malignant  cystic  degenerated  tumor  of  the  hypophysis.  There- 
fore it  seems  that  a  combination  of  multiple  ductless  glandular  sclerosis  and 
hypophysis  tumor  may  occur. 

Up  to  the  present  the  treatment  has  been  of  little  avail.  In  the  cases  of 
Rumpel  and  of  Djeinil  PascJia  the  use  of  thyroid  gland  was  negative,  and  in 
Gonilloud' s  case  doubtful.  French  authors  have  tried  a  combined  ductless 
gland  therapy  (thyroidin,  hypophysis  substance,  sexual  gland  substance,  and 
suprarenal  substance),  and  have  sometimes  seen  temporary  improvement  of 


454  PLURIGLANDULAR    DISEASES 

individual   symptoms   under   the   influence   of   these,   yet   the   progressive 
cachexia  can  for  the  most  part  not  be  essentially  influenced. 

Gigantism 

Historical. — It  can  be  readily  understood  that  gigantism  usurped  the 
interest  of  the  laity  and  physician  from  early  times.  Indeed  a  philanthropist 
even  founded  a  prize  in  order  that  by  the  intermarriage  of  giants  a  larger 
and  stronger  race  would  be  produced.  For  the  first  valuable  scientific  obser- 
vations concerning  this  interesting  phenomenon  we  are  indebted  to  C. 
V.  Langer.  v.  Langer  distinguished  between  normal  and  pathological  giants. 
He  described  three  skeletons  of  normal  giants,  one  from  the  Berlin  Patho- 
logical Institute,  one  from  Hunterian  ^Museum,  and  one  from  Trinity  College, 
Dublin.  These  giants  enjoyed  good  health  until  a  high  age;  they  showed  in 
general  normal  dimensions  of  their  skeletons  corresponding  to  their  size, 
therefore  rather  large  skull  and  a  relatively  large  upper  body,  the  upper 
length  somewhat  exceeding  the  lower  length.  In  the  other  group,  the 
pathological  giants,  v.  Langer  first  pointed  out  that  here  certain  pathological 
alterations  of  the  skeletons  were  present,  such  as  relatively  small  cranium 
with  enlarged  sella  turcica  and  enlargement  of  the  facial  skeleton  with  enor- 
mous lower  jaws,  widening  of  the  pneumatic  spaces,  increased  development 
of  the  insertions  of  the  muscles,  certain  abnormalities  of  the  pelvic  girdle,  fre- 
quency of  genu  valgum,  in  short  a  series  of  alterations  that  to-day  we  would 
designate  as  acromegalic,  v.  Langer  pointed  out  that  from  illustrations  also 
degeneration  of  the  soft  parts,  such  as  enlargements  of  the  tongue  and  the 
lips,  had  existed. 

Then  Sternberg  in  a  detailed  work  pointed  out  the  frequency  of  the  com- 
bination of  acromegaly  and  gigantism.  According  to  Sternberg  about  40 
per  cent,  of  all  giants  are  acromegalics,  and  about  20  per  cent,  of  all  acro- 
megalics giants.  This  cjuestion  entered  upon  a  new  stage  when  especially 
the  French  school  sought  to  define  the  relation  between  acromegaly  and 
gigantism.  After  Massalongo  had  designated  acromegaly  as  late  gigantism, 
Brissaud  and  Meige  came  forward  with  the  teaching  that  acromegaly  and 
gigantism  are  one  and  the  same  disease  and  depend  on  the  same  cause, 
namely,  an  alteration  of  function  of  the  hypophysis,  which  leads  in  youthful 
individuals  to  gigantism,  and  in  older  individuals,  those  in  whom  the  epi- 
physial junctures  have  already  ossifled,  to  acromegah'.  These  authors  also 
sui)port  the  view  that  only  the  acromegalic  giants  should  be  termed  pro]:)er 
giants,  and  that  gigantism  should  always  be  regarded  as  the  disease.  This 
opinion,  which  was  actively  contradicted  by  Pierre  Marie,  Launois  and  Roy 
hav^e  tried  to  support  in  several  researches  and  in  their  monograph. 
These  authors  show,  in  convincing  fashion,  that  the  greater  part  of  the 
giants  thus  far  observed  have  been  acromegalics,  or   have  later    become 


GIGANTISM  455 

acromegalic.     Also    Biedl    has   relegated   the   subject  of  gigantism  to  his 
chapter  on  the  hypophysis. 

Symptomatology  and  Types  of  Gigantism 

According  to  the  opinions  thus  far  existing  in  the  hterature,  as  to  the 
pathology  of  gigantism,  it  is  not  possible  to  define  it  uniformly.  The 
difficulty  begins  already  with  the  question  as  to  which  individuals  should  be 
regarded  as  giants.  Bollinger  proposed  regarding  as  tall,  human  beings 
whose  height  reached  205  cm.,  and  only  speaking  of  giants  when  the  height 
exceeded  205  cm.  This  classification  is  naturally  quite  arbitrary.  Accord- 
ing to  it  a  whole  group  of  the  cases  reported  in  the  literature  would  no  longer 
be  regarded  as  belonging  to  giants.  Just  as  arbitrary  seems  to  me  the 
opinion  occurring  in  the  French  literature  that  only  those  giants  that  bear 
acromegalic  features  should  be  regarded  as  true  giants.  Even  though  well- 
proportioned,  nonacromegafic  giants  are  apparently  among  the  greatest 
rarities,  yet,  according  to  the  definite  statements  of  v.  Langer  and  Virchow, 
their  existence  is  not  to  be  doubted.  Therefore  it  seems  to  me  to  the  point 
to  adhere  to  the  old  classification  of  Langer  and  to  distinguish  between 
normal  and  pathological  giants.  Moreover  we  find  described  in  the  literature 
a  group  of  cases,  whose  height  lay  between  190  and  200  cm. ;  cases  that  showed 
no  acromegahc  features,  but  on  the  other  hand,  all  the  signs  of  typical  eu- 
nuchoidism. Here,  therefore,  there  lies  before  us  all  the  signs  of  a  potentized 
form  of  eunuchoid  tallness,  and  for  this  the  designation  eunuchoid  gigantism 
seems  to  me  not  without  foundation.  The  cases  coincide  in  part  with  those 
cases  which  Launois  and  Roy  have  called  infantile  gigantism.  Considering 
the  fact  that  I  have  sharply  separated  eunuchoidism  from  infantilism — I 
shall  come  back  to  this  differentiation  in  the  next  chapter — I  must  regard 
the  designation  eunuchoid  as  more  precise  than  infantile.  I  would  here 
point  out  that  a  portion  of  the  giants  described  by  Launois  and  Roy  as  in- 
fantile are  not  pure  eunuchoids,  but  already  bear  the  acromegahc  features. 
Finally,  as  to  what  concerns  the  acromegalic  giants  I  shall  take  pains  to  show 
that  here  there  are  very  diverse  types,  those  types  in  which  from  the  be- 
ginning acromegalic  manifestations  are  distinctly  prominent;  those  types 
which  to  use  an  expression  of  Launois  and  Roy  "acromegalize"  only  later; 
those  types  which  possess  the  eunuchoid  features  or  even  pronounced  eu- 
nuchoidism from  youth  on;  those  types  to  whom  a  kind  of  late  eunuchoidism 
comes  only  later,  and  finally  those  types  in  whom  the  eunuchoid  features  are 
entirely  absent,  in  whom,  moreover,  the  function  of  the  sexual  glands  and 
genitalia  are  entirely  normal,  or  even  perhaps  temporarily  abnormally 
increased. 

In  the  great  multiplicity  of  the  manifestations  of  gigantism  a  uniform 
exposition  of  the  symptomatology  is  scarcely  possible;  it  seems  to  me  more 


456  PLURIGLANDULAR    DISEASES 

to  the  purpose  to  adduce  examples  of  the  various  types  from  the  Hterature, 
whereby  I  would  mention  that  all  possible  transitions  between  the  groups 
occur. 

I  will  not  enter  further  into  the  subject  of  normal  giants.  In  the  historical 
introduction  I  have  already  mentioned  the  most  important  facts. 

Of  the  eunuchoid  giants  I  mention  the  twenty-seven-year-old  man 
described  by  Launois  and  Roy.  (Soc.  de  Biol.,  10  Jan.,  v.,  1903.)  In  this 
individual  the  increased  growth  in  height  apparently  began  after  an  attack 
of  typhoid  fever. 

I  shall  now  adduce  a  series  of  cases  relating  to  acromegahc  giants,  in 
whom  the  function  of  the  sexual  glands  was  normal.  As  the  first  example  I 
communicate  a  case  that  I  myself  had  occasion  to  investigate. 

Observation  LV . — B.  O.,  "Bulgarian  giant,"  born  in  Gross-Wenkheim  near  Bad 
Kissingen,  thirty-seven  years  old.  The  male  members  of  the  family  are  almost  all 
rather  tall.  The  tallest  was  his  father's  brother,  who  measured  186  cm.  His  father 
measures  180  cm.  B.  O.  states  that  he  first  began  to  exceed  his  school  companions  in 
growth  at  the  seventh  j^ear  of  life.  At  twelve  years  of  age  he  measured  about  206  cm., 
and  at  twenty-four  years  of  age  had  attained  his  full  height  (212.5  cm.).  He  served  in  the 
"Bayerischer  Leibregiment"  and  was  at  that  time  examined  by  the  chief  physician,  Dr. 
Seggel.  At  that  time  he  was  entirely  well,  and  had  grown  completely  used  to  the  military 
service.  He  says  that  as  a  young  man  he  weighed  145  kg.  Especially  in  his  eighteenth 
to  nineteenth  years  had  his  appetite  become  enormous.  He  says  that  it  was  easy  for  him 
to  devour  at  one  meal  i  kg.  of  meat  with  copious  additional  fare.  The  highest  weight  was 
195  kg.  He  had  never  suffered  from  headache.  According  to  his  statement  the  sexual 
development  was  entirely  normal.  In  1900  he  married  a  woman  who  was  187  cm.  tall. 
After  one  year  she  bore  an  entirely  normally  carried  child,  who  died  after  four  weeks. 
Then  later  the  woman  had  two  premature  deliveries,  about  in  the  fifth  month.  The 
potency  up  to  this  time  had,  according  to  his  statement,  not  diminished.  Six  years  ago 
he  suffered  from  influenza  and  since  that  time  "has  had  to  do  with  a  cough."  The  apex 
of  the  right  lung  is  defective. 

The  man  now  measures  210  cm.  as  a  distinct  kyphosis  exists,  it  is  very  probable  that 
his  statement  that  he  formerly  measured  212.5  cm.  is  perfectly  correct.  The  span  width 
reaches  220  cm.,  the  breadth  of  the  shoulders  52  cm.,  the  circumference  of  the  chest  iiS 
cm.,  of  the  waist  100  cm.  Distance  from  the  anterior  superior  iliac  spine  to  the  floor 
124  cm. 

There  exists,  as  already  mentioned,  distinct  kyphosis,  the  enormous  shoulder  blades 
project  prominently.  The  clavicles  are  enormously  developed.  The  circumference  of  the 
upper  arm  measures  29  cm.,  formerly  when  the  patient  was  very  muscular  it  reached 
68  (?)  cm. 

The  distance  of  the  external  malleolus  of  the  wrist-joint  to  the  point  of  the  middle 
finger  is  27  cm. 

The  greatest  circumference  of  the  hand  is  30.5  cm.  The  greatest  circumference  over 
the  metacarpopharyngeal  joint  is  27  cm. 

The  middle  finger,  from  the  metacarpopharyngeal  joint  to  the  point  of  the  finger  is  14 
cm.,  the  circumference  of  the  thumb  9  cm. 

Distance  between  the  anterior  superior  spine  and  the  upper  Ix^rder  of  the  patella  is 
57  cm.;  length  of  foot  33.5  cm.  Circumference  around  the  ankle-joint  and  heel  43  cm.; 
length  of  great  toe  9.5  cm.;  circumference  of  the  same  11  cm.     The  head  is  enormous. 


GIGANTISM 


457 


Fig,  79.— Gigantism    (Observation   LVj    and    hypophysial    dwarf    (Observation    XLI\'i.     The 

normal  individual  measures  183  cm. 


458  PLURIGLANDULAR    DISEASES 

The  fronto-occipital  circumference  reaches  67  cm.  The  occipitomental  circumference  73 
cm.  The  superciliary  arches  project  markedly,  as  do  also  the  malar  ones.  There  exists 
distinct  prognathia.  The  anterior  upper  incisors  are  1.5  cm.  from  each  other.  The  set  of 
teeth  is  normal;  only  one  tooth  is  absent.  The  tongue  is  disproportionately  large.  The 
palate  is  in  proportion.  The  least  circumference  of  the  neck  is  42  cm.  The  pomum  Adami 
projects  markedly.  The  thyroid  gland  is  palpable  and  is  in  proportion.  The  voice  is 
very  deep  and  low.  The  hairiness  is  very  abundant.  The  mustache  is  well  developed, 
the  man  must  shave  every  two  days.  The  chest  and  the  linea  alba  are  extensively  pro- 
vided with  hair.  Also  the  hairiness  on  the  genitals  and  the  perineum,  and  in  the  axillje  is 
abundant.  The  genitalia  are  proportioned  to  the  other  relations.  Heart  dulness;  upper 
border  of  the  fifth  rib,  left  sternal  bojd-er,  7  J-^  cm.  to  the  left  of  the  border  of  the  sternum. 
Heart  sounds  clean     Slight  tachycardia  (105). 

The  orthodiagram  shows  a  greatest  heart  breadth  of  13  cm.,  breadth  of  the  aortic 
shadow  7  cm.  These  measurements  are  relatively  very  small.  Tuberculous  affection  of 
both  apices.  The  stomach  is  enormously  large,  sac-like,  reaches  20  cm.  below  the  navel. 
The  ordinary  bismuth  meal  is  just  enough  to  fill  the  fundus  of  the  stomach. 

Blood  examination:  Hemoglobin  (according  to  Saldi),  80  per  cent. 
Erythrocytes,  5,720.000 
Leucocj^tes,  5600,  of  which: 
Neutrophilic  polymorphonuclear,  65  per  cent. 
Lj^mphocytes,  20  per  cent. 
Large  mononuclears,  9  per  cent. 
Eosinophiles,  6  per  cent. 

The  examination  of  the  urine  shows  sugar  o,  albumin  o,  urobilin  o,  indican  +. 

Eye  examination  {Dr.  Ulbrich).  The  pupillary  distance  is  72  mm.  (normal  about  65 
mm.).     The  length  of  the  palpebral  fissures  a  mm.  (normal  28  mm.). 

On  the  contrary  we  find  that  globes  lie  abnormally  free  on  all  sides  and  that  the  width 
of  the  cornea  is  not  greater  than  the  normal  average  (11  mm.).  Eye-grounds  normal. 
Visual  field  and  color  field  normal. 

The  X-ray  plate  of  the  hand  shows  entirely  normal  ossification.  The  enlargement 
affects  bones  and  soft  parts  rather  to  a  like  degree. 

The  X-ray  plate  of  the  head  shows  enormous  relations.  We  see  the  frontal  and  the 
maxillary  sinuses  considerably  broadened  and,  further,  the  distinct  prognathia  of  the  lower 
jaw.  The  bones  of  the  cranial  vault  are  enormously  thickened,  the  sutures  markedly 
projecting,  especially  striking  is  the  enormous  external  occipital  protuberance. 

The  sella  is  markedly  enlarged  and  deepened;  the  posterior  clinoid  processes  are  dis- 
tinct, and  the  anterior  less  evident.  The  introitus  of  the  sella  is  relatively  not  very 
wide  (Fig.  80). 

We  are  hence  dealing  in  this  case  with  a  typical  acromegalic  giant. 
The  acromegalic  tendency  became  evident  at  a  rather  early  age  and  seems 
to  have  progressed  very  gradually.  At  least  this  man  can  give  no  sure 
statement  as  to  when  the  coarsening  of  the  features  and  the  prognathia  be- 
gan to  develop.  He  states  that  his  hands  and  feet  have  not  become  essen- 
tially larger  in  the  last  ten  years.  We  have  better  data  so  far  as  the  kyphosis 
is  concerned.  During  the  military  service,  hence  fourteen  years  ago,  this 
did  not  exist.  Another  point  is  furnished  by  the  diminution  of  muscular 
strength,  which  at  about  the  twentieth  year  must  have  been  enormous. 
The  pulmonary  tuberculosis  that  has  developed  in  the  last  year  can  surely  be 


Fig.  8o. — Skull  of  a  giant  (Observation  LV). 


GIGANTISM  459 

held  responsible  for  only  a  small  portion  of  the  decay.  Signs  of  increased 
intracranial  pressure  are  not  as  yet  present  in  this  patient;  with  which  the 
X-ray  findings — these  show  especially  a  deepening  of  the  floor  of  the  sella, 
are  in  accord.  Especially  important  in  this  case  is  the  behavior  of  the 
sexual  glands.  The  functions  of  the  genitalia  up  to  the  present  time  have 
been  entirely  normal.  At  all  events  up  to  his  thirtieth  year  the  patient 
was  capable  of  reproduction.  At  most  we  could  say  that  the  early  death  of 
the  first  child  and  the  two  following  premature  deliveries  on  the  part  of  his 
wife  point  to  a  diminished  valuation  of  the  semen,  but  this  assumption  does 
not  seem  to  me  to  be  well  considered.  In  agreement  with  the  sexual  po- 
tency we  find  the  dimensions  of  the  skeleton  normal,  and  the  hairiness  even 
abnormally  strongly  developed. 

Also  the  giant  of  Hiichard  and  Launois  had  two  children.  In  this  case 
the  abnormal  increase  in  growth  began  in  the  twelfth  year  of  life.  At  the 
age  of  eighteen  he  was  197  cm.  tall.  The  genitalia  were  entirely  normally 
developed.  He  attained  the  age  of  sixty  years  and  at  that  time  showed  typical 
acromegalic  manifestations.  The  sella  turcica  was  the  size  of  a  nut.  Sclero- 
sis of  the  anterior  lobe  was  found  at  autopsy.  This  case  has  been  brought 
forward  as  a  demonstration  against  the  hyperf unction  theory  of  acromegaly. 
Incorrectly  however,  for  we  may  well  imagine  that  in  late  life  the  acromegahc 
manifestations  must  not  necessarily  retrogress  when  there  occurs  without  any- 
thing else  a  secondary  sclerosis  of  the  hypophysis. 

The  case  of  Buday  and  Jancso  showed  an  abnormal  increase  of  the 
potency  that  was  at  all  events  short  in  duration.  At  seventeen  years  of 
age  this  patient  was  very  potent,  and  performed  coitus  four  to  six  times 
every  night.  From  the  twentieth  year  on  he  gradually  became  impotent. 
It  is  noteworthy  that  this  case  was  only  103  cm.  tall  when  he  was  twenty 
years  old.  Now  he  first  began  to  grow  appreciably,  and  at  the  age  of  thirty-  ' 
five  years  had  attained  the  height  of  198  cni.  He  now  showed  distinct 
acromegalic  symptoms;  there  was  found  a  large  tumor  of  the  hj-pophysis, 
the  genitaHa  were  atrophied,  the  length  of  the  lower  part  of  the  body  was 
very  considerable,  there  existed  a  genu  valgum,  the  epiphysial  junctures 
were  ossified  (the  abnormal  growth  has  ceased  for  two  years).  In  this  case 
we  have  the  sort  of  late  eunuchoidism  combined  with  acromegaly.  It  is 
very  noticeable  that  in  spite  of  the  increased  sexual  function,  the  epiphysial 
junctures  remained  open  between  the  seventeenth  and  twentieth  years. 

I  would  regard  the  case  described  by  Gushing  as  one  in  which  the  late 
eunuchoidism  began  later.  This  thirty-five-year-old  patient  came  from  a 
healthy  family.  The  father  was  six  feet  tall.  At  the  age  of  thirteen  years 
the  patient  first  began  to  grow  enormously  rapidly;  at  the  age  of  nineteen 
years  he  was  6  ft.  4  in.  tall,  weighed  200  lb.  and  was  of  extraordinary  strength, 
and  he  was  intelligent,  a  good  student,  and  "aside  from  an  uncontrolled 
libido  sexuahs"  had  good  manners.     Especially  noteworthy  seems  to  me 


460  PLURIGLAXDrLAR    DISEASES 

the  fact  that  only  latterly  did  the  obesity  that  occurred  assume  the  eu- 
nuchoid type  (as  far  as  I  can  see  from  pictures).  This  is  true  also  of  the 
absence  of  beard,  and  the  eunuchoid  hairiness.  "He  has  practically  no 
beard,  and  except  for  a  scant  pubic  growth  of  feminine  distribution,  the 
skin  of  the  trunk  and  extremities  is  practically  hairless."  The  hair  of  the 
head  was  abundant. 

Also  in  the  case  described  by  Levi  and  Frauchini  did  there  occur  a  late 
eunuchoid  obesity. 

The  abnormal  growth  began  in  this  person,  who  was  sixty-five  years  old,  at  the  age  of 
eight  to  ten  years,  the  secondary  sexual  characters  were  apparently  normally  developed  at 
the  time  of  pubertj^  there  were  few  erections,  however,  and  there  never  had  existed  an 
especial  libido.  The  external  genitalia  were  normal,  as  was  also  the  mental  development. 
He  was  always  weak  muscularly,  in  the  last  few  years  obesity  developed,  the  distal  parts  of 
the  extremities  showed  a  considerable  enlargement,  there  existed  cervicodorsal  kyphosis, 
in  short  the  signs  of  an  acromegaly  that  had  gradually  developed  over  a  long  period  of 
time.     The  epiphysial  junctures  were  closed. 

I  now  adduce  several  examples  of  the  eunuchoid  type,  in  which  the 
symptoms  of  deficiency  on  the  part  of  the  sexual  glands  already  exerted  an. 
influence  on  skeletal  formation  in  early  youth.  Here  belongs  the  giant 
Charles  described  by  Launois  and  Roy.  In  the  thirtieth  year  of  his  life, 
his  height  was  204  cm.  The  lower  length  was  considerably  more  than  the 
upper  length.  The  penis  was  small,  the  testicles  were  very  small,  and  the 
prostate  also  was  small.  He  had  had  on  several  occasions  erections,  but 
never  ejaculations.  The  hairiness  of  the  trunk  was  typically  eunuchoid. 
The  epiphysial  junctures  were  entirely  open.  In  later  life,  acromegalic 
features  made  their  appearance. 

A  pronounced  case  is  reported  by  Cushing  that  on  account  of  the  mon- 
strosity present  I  shall  herewith  adduce;  thirty-six  year-old  man;  he  was  al- 
ready as  a  boy  abnormally  tall,  and  from  the  fifteenth  year  on  grew  enormously. 
For  ten  years  he  has  been  sick  and  weak.  At  autopsy  the  body  measured 
251.5  cm.,  the  skin  is  delicate,  hairness  of  the  head  good,  no  growth  of  beard, 
no  axillary  hairiness,  sparse  hairiness  of  the  pubic  region.  The  genitaha  are 
small,  the  testicles  atrophied.  The  distal  epiphysial  juncture  of  the  radius 
is  still  open,  no  alimentary  glycosuria.  Distinct  symptoms  of  acromegaly  are 
present.  The  sella  turcica  is  very  much  enlarged  (2.2  to  2.7  cm.)  and  the 
hypophysis  consists,  in  great  part,  of  a  cyst. 

Again,  in  such  eunuchoid  giants  the  acromegalic  alterations  may  be  very 
significant.  There  are  also  known  female  eunuchoid  giants.  As  example  I 
adduced  Lady  Aama,  described  by  Woods  Ilulchiiison.  She  was  about 
seventeen  to  nineteen  years  old,  244  cm.  tall,  and  the  lower  length  far  ex- 
ceeded the  upper  length ;  hands  and  lower  jaw  were  very  large.  The  genitalia 
were  infantile,  the  mons  Veneris  was  poorly  developed,  the  labia  majora  were 
flat,  the  clitoris  was  well  developed  and  resembled  a  poorly  developed  penis. 


GIGANTISM  461 

The  ovary  on  each  side  was  very  small,  and  changed  into  glandular  masses. 
The  hypophysis  was  enlarged,  the  sella  turcica  was  destroyed,  the  mammae 
were  entirely  hypoplastic. 

I  believe  that  the  examples  I  have  furnished  sufi&ce  to  show  the  enormous 
multiplicity  of  the  manifestations  of  the  pathological  forms  of  giant  growth. 
The  symptoms  of  eunuchoidism  or  late  eunuchoidism  are  combined  with 
those  of  acromegaly  in  the  most  diverse  ways.  If  we  disregard,  however, 
the  quite  rare  cases  of  pure  eunuchoid  gigantism,  we  find  indeed  that  the  mani- 
festations of  eunuchoidism  and  late  eunuchoidism, are  very  common,  while 
the  manifestations  of  acromegaly  are  present  almost  always  regularly,  or 
that  they  develop  later.  In  this  connection  the  classification  of  pathological 
giants  of  Launois  and  Roy  is  very  correct,  even  if  it  is  not  just  to  the  uncom- 
monly numerous  types. 

Pathogenesis. — If  we  now  turn  to  a  pathogenesis  of  gigantism,  our 
first  task  will  be  to  test  whether  the  formula  of  Brissattd-Meige,  which  also 
has  been  adopted  by  Launois  and  Roy,  is  in  the  position  to  explain  the  mani- 
fold types  of  gigantism.  Brissaud  and  Meige  have  expressed  the  opinion 
that  gigantism  is  nothing  other  than  an  acromegaly  beginning  in  early 
youth,  that  is,  before  the  closure  of  the  epiphyses.  A  great  difference  be- 
tween acromegaly  and  pathological  gigantism  exists,  first  of  all,  in  the  be- 
havior of  the  sexual  glands.  I  must  here  again  point  out  the  fundamental 
difference  in  the  relation  of  the  glands  of  generation  and  the  interstitial 
glands  in  typical  acromegaly.  The  first  show  temporary  increase  of  their 
function,  but  then  there  very  commonly  occurs  very  premature  disturb- 
ances or  entire  loss  of  their  function,  whereas  the  function  of  the  interstitial 
glands  is  rather  more  emphasized,  or  at  all  events,  apart  from  very  rare  cases, 
shows  no  disturbance  in  the  course  of  the  disease.  In  gigantism  we  see  this 
behavior  in  but  a  few  cases.  In  the  majority  of  cases  the  manifestations  of 
eunuchoidism  are  prominent  from  the  beginning,  or  later  there  occur  mani- 
festations of  late  eunuchoidism.  In  the  description  of  early  acromegaly  a 
similar  behavior  of  the  sexual  glands  has  been  noted. 

There  cases  were  described  in  which  also  the  interstitial  glands  showed  dis- 
turbances of  their  function,  in  this  respect  lending  countenance  to  the  Brissaud - 
Meige' s  formula.  There  also  we  learned  about  sure  cases  of  acromegaly,  that 
came  to  manifestations  of  acromegaly  while  the  epiphysial  junctures  were  still 
open.  Increase  of  function  of  the  hypophysis  alone,  hence,  does  not  lead  to 
gigantism.  We  must  assume  in  addition  to  it  a  potential  tendency  to  growth, 
that  may  be  either  proportionate  (normal  giants),  or  as  it  is  mostly,  dispro- 
portionate, partly  through  a  preponderance  of  the  function  of  the  hypophysis, 
partly  through  an  insufficiency  of  the  interstitial  glands  and  probably  also 
through  many  other  factors.  While  in  acromegaly  we  certainly  find  a 
tendency  to  hyperfunction  and  hyperplasia  of  other  ductless  glands  in  which, 
however,  always  the  increase  in  function  of  the  hypophysis  remains  quite  in 


462  PLURIGLANDULAR    DISEASES 

the  foreground,  in  gigantism  the  tendency  to  increase  in  function  of  the  whole 
ductless  glandular  system  seems  to  belong  quite  to  the  essence  of  the  disease. 
It  would  seem  that  in  addition  to  the  hypophysis  all  the  ductless  glands  are 
involved  in  a  predominant  manner  in  the  hyperplasia — the  suprarenal  cortex, 
probably  also  the  chromaffin  tissue,  etc.  How  enormous  the  pancreas  may 
become  is  shown  by  the  autopsies  of  the  giants  Bassoe  Peter  and  of  the  Tam- 
bourmajor.  The  pancreas  of  the  former  weighed  275  gm.,  that  of  the  latter 
250  gm.  Also  the  sexual  glands  may  be  involved  in  this  hyperplasia.  In 
addition  to  this  tendency  to  hyperplasia  there  exists,  however,  a  lability,  a 
ready  exhaustibility  of  the  hyperplastic  ductless  glandular  system;  this 
seems  to  affect  the  most  readily  the  sexual  glands,  in  which  degenerative 
processes  may  be  established  prematurely,  indeed  under  circumstances  the 
sexual  glands  (and  especially  the  interstitial  glands  which,  indeed  differ  from 
the  other  ductless  glands  in  that  they  attain  full  maturity  not  until  the  time 
of  puberty)  may  be  disturbed  in  their  development  from  the  beginning. 
Also  the  development  of  the  nervous  system  may  suffer  damage  from  this  fact. 
The  monstrous  eunuchoid  giants  are  the  most  deficient  mentally.  In  addi- 
tion to  the  sexual  glands  the  other  ductless  glands  mostly  rapidly  show  signs 
of  decay.  The  frequency  of  diabetes  in  youthful  giants  is  known.  In 
the  great  decrepitude  and  muscular  weakness  perhaps  there  is  involved  a 
degeneration  of  the  chromaffin  tissue.  Even  in  the  hypophysis,  such  de- 
generative processes  frequently  occur,  if  the  individuals  attain  a  high  enough 
age.  I  refer  to  the  case  of  Hudiard  and  Laiuiois  in  which  the  hypophysis 
was  found  to  be  sclerotic,  or  to  that  of  Cushing  in  which  the  hypophysis 
was  in  great  part  converted  into  a  cyst.  How  rapidly  the  decay  can  enter 
in  just  these  monstrous  giants  is  shown  by  numerous  cases  in  the  literature. 
The  enormous  muscular  power  of  which  these  individuals  were  wont  to  be  so 
proud  gives  place  in  a  few  years  to  a  great  weakness.  The  ductless  glandular 
system  has  exhausted  itself  and  the  organism  fades  rapidly  like  a  plant 
driven  to  rapid  growth  by  artificial  means.  Mostly  the  invalidism  is  rapidly 
made  an  end  to  by  an  intercurrent  disease.  Woods  Hutchinson  tells  of 
eight  giants  that  died  on  the  average  in  their  twenty-first  year  of  life. 

Investigations  of  the  respiratory  metabolism  of  giants,  as  well  in  the 
time  of  bloom  as  in  that  of  decay,  would  be  very  important.  I  do  not  know 
of  any  of  them.  With  regard  to  the  other  metabolism  investigations,  there 
are  only  the  statements  of  Levi  and  Francliini,  who  in  one  case  found  increase 
of  the  elimination  of  amino-acids,  ammonia,  and  neutral  sulphur. 

On  the  basis  of  what  has  been  said  above,  I  would  assume  in  gigantism 
an  abnormal  mapping-out  [Anlage]  of  the  whole  ductless  glandular  system, 
and  would  not,  as  have  other  authors,  simply  include  it  in  the  chapter  on 
acromegaly.  We  know  indeed  that  there  are  other  forms  of  gigantism 
setting  in  in  early  life  in  which  not  the  hypophysis,  but  other  ductless  glands 
(the  epiphysis,  the  suprarenal  cortex,  the  sexual  glands)  occupy  the  chief 


GIGANTISM  463 

role  in  the  pathogenesis.  In  such  cases  there  may  indeed  appear  even 
simultaneous  manifestations  of  hypophysial  insufficiency  (confer  the  case 
of  Raymond  and  Claude).  But  as  I  mentioned  already  at  the  beginning 
the  conception  does  not  seem  to  me  established  as  yet.  I  must  leave  open 
the  question  as  to  whether  the  hyperplastic  mapping  out  of  the  entire  duct- 
less glandular  system  is  only  a  partial  phenomenon  of  an  abnormal  mapping 
out  of  the  entire  organism.  We  know  indeed  of  a  gigantism  of  individual 
extremity  masses.  I  refer  to  the  communications  of  Fischer^  Manasse, 
Wiedenmann,  Grunfeld,  et  al.  We  cannot  hold  the  ductless  glandular  system 
responsible  for  such  an  abnormal  growth  tendency,  even  though  there  are 
found,  also  not  rarely,  certain  anomalies  of  this  system,  e.g.,  cryptorchidism 
on  the  same  side. 

^Addendumj 

Parhon  and  Parhon  would  add  paralysis  agitans  to  the  list  of  pluriglan- 
dular diseases  on  the  strength  of  certain  Abderhalden  tests  in  which  the  duct- 
less glandular  extracts  in  general,  but  especially  those  of  thyroids  and  para- 
thyroids, reacted  positive  to  the  sera  of  paralysis  agitans  patients. 

Reference 

Parhon  (C.S.),  and  Parhon  (M.) :  Untersuchungun  tiber  die  Abderhaldensche  Reaktion 
bei  der  Parkinsonschen  Krankheit.  Fermentforschung,  Vol.  i,  No.  3.,  p.  311-314. 


CHAPTER  XII 

VEGETATIVE  DISTURBANCES,  NOT  DIRECTLY  DEPENDENT  ON 
DISEASES  OF  THE  DUCTLESS  GLANDS 

The  words  "vegetative  disturbance"  [Vegetationstorung]  to  my  knowl- 
edge originated  with  Kundrat.  By  them  we  understand  any  inhibition  of  de- 
velopment. Since  the  time  it  was  known  that  the  growth,  and  especially 
the  normal  development  of  the  organism  was  guaranteed  only  by  a  normal 
development  of  the  ductless  glandular  system,  modern  investigation  has 
been  directed  toward  seeking  the  cause  of  the  different  vegetative  disturb- 
ances in  the  ductless  glandular  system.  In  the  foregoing  chapters  an  entire 
s'eries  of  vegetative  disturbances  were  comprehended,  which  to-day  we  are 
justified  in  regarding  as  referable  to  a  functional  disturbance  of  individual 
ductless  glands.  It  seems  important  for  the  following  exposition,  again 
briefly  to  sketch  what  these  are: 

1.  Absence  of  the  thyroid  leads  to  dwarfism;  in  this  is  found  characteristic 
disturbances  of  ossification,  consisting  in  a  high-grade  remaining  behind  in 
development  of  the  bone  nuclei,  and  in  the  closure  of  the  epiphyses,  further 
in  a  disturbance  in  development  of  the  bone  marrow;  what,  however,  has 
already  been  formed  of  the  bones  is  of  abnormal  hardness;  further  there  are 
found  disturbances  in  the  dentition,  and  in  development  of  the  central 
nervous  system,  whereby  the  development  of  the  intelligence  suffers. 
Further  there  are  found  the  characteristic  myxedematous  alterations  of  the 
skin,  and  disturbances  in  the  development  of  the  genitalia. 

2.  The  vegetative  disturbances  in  endemic  cretinism  is  not  dependent 
alone  on  the  goitrous  degeneration  of  the  thyroid  gland.  It  is  far  more 
likely  that  the  deleterious  agent  acts  also  directly  on  the  central  nervous 
system  and  on  other  ductless  glands,  for  instance,  the  hypophysis.  Thereby 
the  vegetative  disturbances  are  extremely  manifold,  the  individuals  remain 
very  much  behind  in  growth,  but  the  disturbance  in  ossification  is  not 
disproportionate;  one  time  the  developmental  disturbances  of  the  central 
nervous  system  may  stand  in  the  foreground,  another  time  the  inhibition  in 
growth,  and  another  time  perhaps  the  disturbances  in  the  development  of 
the  hypophysis. 

3.  Pronounced  inhibition  of  development  is  found  also  in  diseases  of  the 
hypophysis  that  develop  in  early  youth.  In  this  case  there  occur,  at  least 
in  a  suggestive  manner,  eunuchoid  dimensions  on  account  of  a  prominent 
developmental  inhibition  of  the  sexual  glands,  and  further  there  occurs 
eunuchoid  distribution  of  fat.     Disturbances  in  the  development  of  the  bone 

464 


INFANTILISM  465 

nuclei  and  of  the  epiphysial  junctures  occur  distinctly  only  in  most  severe 
cases.  The  intelligence  develops  normal,  although  these  individuals  show 
the  characteristic  temperamental  attitude. 

4.  Again,  disturbances  in  the  development  of  the  suprarenal  cortices  per- 
haps also  lead  to  definite  vegetative  disturbances;  very  little  clearness  as  to 
this  point  exists,  however. 

5.  Isolated  disturbances  in  the  development  of  the  sexual  glands  leads  to 
eunuchoidism  with  characteristic  distribution  of  fat,  characteristic  dimensions 
of  the  skeletons,  remaining  open  of  the  epiphysial  junctures,  especially  those 
that  close  latest  under  normal  conditions,  and  a  characteristic  psychic 
attitude  with  normal  development  of  the  intelligence. 

There  remains  now  a  group  of  vegetative  disturbances  that  of  late  have 
frequently  been  brought  into  association  with  the  diseases  of  the  ductless 
glands.  In  some  of  these  the  relation  to  the  ductless  glandular  system  is  not 
yet  sure,  in  others,  the  disturbances  on  the  part  of  the  ductless  glands  consti- 
tute only  one  component  of  the  clinical  picture.  Finally  in  others  I  would 
deny  the  connection.  In  this  great  group  of  vegetative  disturbances  I  would 
include  true  infantilism,  true  dwarfism,  chondrodystrophy,  rachitic  dwarfism, 
and  Mongolism.  In  the  exposition  of  each  disease,  its  relation  to  the 
ductless  glandular  system  will  be  especially  considered.  We  shall  not  enter 
further  into  the  subject  of  dwarfism  in  microcephalus  and  porencephalus. 
I  have  described  dwarfism  with  hydrocephalus  in  the  chapter  on  hypophysial 
dystrophy. 

I.  INFANTILISM 

Historical. — The  first  cases  of  human  beings  who  for  their  life  time  re- 
mained in  a  childish  stage  of  development  [pathologically]  were  described 
by  Dancel  and  Baillarger.  The  case  of  Dancel  was  that  of  a  woman  twenty- 
four  years  old  who  was  94  cm.  tall  and  showed  a  mental  and  physical  develop- 
ment of  a  four-  to  five-year-old  child.  Lasegue  coined  the  name  infantilism 
[-us].  He  understood  by  it  a  condition  of  persistence  in  the  adult  of  the  psy- 
chical and  physical  characteristics  of  a  child.  The  first  exact  description  was 
made  by  Lorain.  He  describes  a  form  of  infantilism  that  he  describes  as 
''Characterisee  par  la  debihte,  la  gracilite  et  la  petitesse  du  corps,  par  une 
sorte  d'arret  de  developpement,  qui  porterait  plutot  sur  la  masse  de  I'individu 
que  sur  un  appareil  speciale:  en  un  mot  des  subjets  atteint  d'une  juvenilite 
persistente  qui  retarde  indefiniment  chez  eux  I'establissement  integral  de 
la  puberite."  Lorain  and  his  pupil  Faneau  de  la  Cour  already  stated  that 
the  different  harmful  influences  that  may  affect  the  juvenile  organism 
may  lead  to  infantilism. 

The  question  has  been  especially  discussed  in  the  French  and  Italian 
literature,  ever  since  Brissaud  set  forth  a  form  of  infantilism  that  he  referred 
to  as  insufficiency  of  the  thyroid  gland  in  child  life.  Brissaud  considers  that 
30 


466  VEGETATRE    DISTURBANXES 

the  type  Lorain  constitutes  a  dystrophic  condition,  and  is  brought  about  and 
maintained  by  a  chronic  congenital  or  inherited  disease  during  the  period  of 
growth. 

The  views  of  Brissaiid  have  been  adopted  in  recent  time  by  Bauer.  Bauer 
regards  only  the  t\'pe  Brissaud  as  true  infantilism  and  separates  all  other 
forms  from  the  tj-pe  Brissaud  as  "chetivisme."  Hertoghe  and  Ausset- 
Breton  go  still  further  than  Brissaud;  they  see  in  all  forms  of  infantilism  an 
expression  of  a  congenital  damaging  of  the  function  of  the  thyroid  gland  and 
thus  seek  to  estabhsh  all  forms  on  a  uniform  basis. 

Ferrani)ii  was  the  first  to  oppose  this  view.  Ferranini  separates  the 
two  forms  of  infantilism,  and  regard  the  type  Lorain  as  the  sequel  of  a 
developmental  deformity,  and  the  type  Brissaud  as  the  sequel  to  the  stand- 
still of  development.  Ferranini  sets  forward  the  significance  of  the  con- 
genital or  early  inherited  heart  defect  in  the  pathogenesis  of  infantilism 
(cardiodystrophic  infantilism).  Carre  and  Gilbert  and  Rather y  hold  similar 
views.  In  recent  time,  especially  E.  Levi  has  opposed  the  views  of  Brissaud, 
in  that  he  mentions  that  not  all  the  true  infantilisms  are  to  be  referred  to  an 
insufliciency  of  the  thyroid  gland.  The  type  Lorain  should  also  be  regarded 
as  true  infantilism.  Before  this  Sante  de  Sanctis  had  already  again  sharply 
separated  the  two  t}-pes  and  emphasized  the  significance  of  various  factors  for 
the  genesis  of  the  type  Lorain,  factors  such  as  hypoplasia  of  the  vessels, 
chlorosis,  disposition  to  tuberculosis,  hereditary  syphilis,  malaria  acquired 
in  early  youth,  pellagra  of  the  parents  (Agostini),  etc.;  furthermore,  de 
Sanctis  separated  the  true  form  of  psychic  infantilism  from  idiocy.  Then, 
too,  de  Sanctis  was  the  first  to  attempt  to  explain  the  genesis  of  the  t}'pe 
Lorain  through  alterations  in  the  ductless  glandular  system.  The  delay  in 
the  physical  and  psychical  development  is  never  the  result  of  isolated 
alteration  of  an  individual  ductless  gland,  but  is  produced  by  a  ''deviation 
de  la  fonction  harmonique  formative-protectrice  de  toute  les  glandes  a 
secretion  interne."  In  an  interesting  study,  R.  Anton  has  described  the 
psychic  side  of  infantilism.  General  infantilism  was  defined  by  Anton  as 
"a  developmental  disturbance,  that  causes  the  entire  organism  to  remain 
behind  at  the  child  txpe,  but  prevents  the  reproduction  of  the  individual  in 
the  sense  of  this  species.  Thereby  not  only  the  physical  earmarks,  but  often 
also  the  psychical  characteristics  of  the  child  persist." 

With  general  infantilism  Anton  includes: 

A.  The  infantilism  with  myxedema  and  cretinism. 

B.  Mongolism. 

C.  Infantilism  through  absence  or  atrophy  of  the  genitalia. 

D.  Infantilism  with  primary  lesion  of  the  visceral  glands,  especially  the 
suprarenals,  the  thymus  gland,  and  the  pancreas. 

E.  InfantiHsmus  dystrophicus,  with  the  following  etiological  variation: 
Infantilism  in  vascular  aplasia. 


INFANTILISM  467 

in  primary  brain  lesions,  unilateral  or  bilateral; 

in  hereditary  syphilis; 

in  alcohoHsm  or  other  poisonings  (lead,  mercury,  etc.)  of  the  parents; 

in  other  diseases  and  metabolic  disturbances  that  are  acquired  early, 
such  as  tuberculosis,  chlorosis,  and  cardiac  defects; 

through  deformities  due  to  bad  hygienic  surroundings  and  to  insufh- 
cient  nourishing  of  the  child. 

Of  partial  infantiHsm,  I  mention  especially  the  infantihsm  consisting  in 
an  atrophy  of  the  genitalia,  and  the  pure  psychical  infantilism. 

I  would  finally  especially  emphasize  here  the  excellent  studies  of  di 
Gasperos.  Here  we  find  five  cases  described  in  detail,  which,  as  we  shall  see 
later,  are  fine  examples  of  true  infantilism.  Di  Gasperos  handles  with  special 
care  the  psychical  side  of  the  problem. 

Schuller  divides  infantilism  into  two  forms:  He  distinguishes  a  dys- 
trophic form  conditioned  by  hereditary  diseases,  or  diseases  acquired  in 
early  youth,  and  a  form  whose  pathogenesis  is  seen  to  depend  on  a  lesion  of  a 
definite  ductless  gland  (thyroid,  hypophysis,  etc.). 

The  regular  undevelopment  of  the  genitals  in  the  type  described  hy  Lorain 
has  induced  many  authors  to  term  "infantilism"  the  most  varying  patho- 
logic states  in  which  the  genitalia  remain  more  or  less  hypoplastic.  Thus 
we  find  in  the  literature  numerous  cases  of  true  gigantism  published  under 
the  title  infantilism  plus  gigantism.  Further  we  find  published  numerous 
cases  of  infantilism  whose  description  would  correspond  to  that  which  in  a 
former  chapter  we  have  regarded  as  eunuchoids,  or  cases  that  at  all  events 
must  be  regarded  as  transition  forms  between  eunuchoids  and  true  in- 
fantiles.  This  is  especially  the  case  in  the  new  expositions  of  the  subject 
by  Peretz  and  by  Pende.  In  the  work  of  Peretz  we  find  nearly  all  the  duct- 
less glandular  diseases  associated  with  developmental  disturbances  classified 
as  infantilism.  Even  infantile  features  are  ascribed  to  hypergenitalism. 
Gandy  terms  "infantilism  reversif  ou  tardif"  cases  in  which  after  com- 
pleted development  a  retrogression  of  the  genitalia  and  the  secondary 
sexual  characters  begins  (confer  "late  eunuchoidism,"  Chapter  X).  The 
ductless  glandular  theory  has  found  an  especially  ardent  advocate  in  Pende, 
who  assumes  as  the  cause  of  infantilism  a  disease  of  the  ductless  glandular 
system.  He  bluntly  calls  infantilism  a  disease  of  the  ductless  glandular 
system,  and  arrays  himself  against  the  opinions  advocated  by  Anton  and 
others,  that  there  is  also  an  infantilism  that  is  dystrophic  ectoglandular, 
and  independent  of  a  disease  of  the  endocrine  glands. 

We  see  then,  that  there  is  hardly  an  idea  in  the  medical  Hterature  con- 
cerning which  there  is  more  confusion  than  that  pertaining  to  infantilism. 

The  name  infantilism  can  surely  readily  give  occasion  to  misunder- 
standings because  in  any  kind  of  inhibition  of  development,  infantile  features 
mav  be  retained.     I  believe,  however,  that  a  clear  definition  is  possible  if  we 


468 


VEGETATIVE    DISTURBANCES 


limit  ourself  to  the  thought  that  the  childish  organism  is  characterized  not 
only  by  the  still  undeveloped  genitalia  and  the  childish  mentality,  but,  as 
already  Breus  and  Kolisko  mention,  by  definite  childish  dimensions. 

Definition. — We  may  therefore 
briefly  define  a  pure  infantilism  as  a 
standing  still  at  the  infantile  stages  of 
development,  considering  especially  the 
following  factors:  the  genitalia  and  the 
vita  sexualis  remain  undeveloped,  or  de- 
velop deficiently;  and  the  same  is  true 
of  the  secondary  sexual  characters;  the 
involution  of  the  lymphatic  apparatus  is 
deficient,  the  growth  is  deficient,  ossifi- 
cation, that  is,  the  appearance  of  the 
bone-nuclei  and  the  closure  of  the  epiphy- 
ses is  delayed,  and  the  childish  di- 
mensions of  the  body  are  retained 
wholly  or  in  part;  that  is  the  lower  length 
of  the  body  equals  the  upper  length  or, 
what  is  commoner,  exceeds  it  only  a 
little,  the  form  of  the  pelvis  is  neither 
[of  the]  masculine  or  feminine  [type], 
but  infantile,  and  finally  the  psyche 
remains  behind  [in  development].  Such 
individuals  show  throughout  no  gross 
defect  in  intelligence,  but  their  minds 
remain  childish. 

Important  for  the  definition  of  in- 
fantilism are  the  following  considera- 
tions, which  serve  to  render  precise  the 
position  of  the  ductless  glandular  sys- 
tem in  the  pathogenesis  of  infantilism. 
If  the  infantilism  comes  about  through 
a  standstill  of  the  entire  organism  at  a 
child  stage  of  development,  then  it  is 
intelligible  that  also  the  sexual  glands 
do  not  develop  further.  Up  to  the 
present  however  we  have  not  sufficiently 
considered  that  the  sexual  glands  occupy 
a  separate  jiosition  in  the  ductless  glandu- 
lar system,  in  that,  though  they  functionate  from  early  youth  and  influence 
the  development  of  the  organism,  yet  they  attain  their  complete  maturity 
only  at  the  age  of  puberty;  the  other  ductless  glands  are  already  fully  de- 


'J 


\ 


V>v 


Fig.  8i. — True  infantilism  (Observation TA^I). 


INFANTILISM  469 

veloped  in  the  new-born.  At  the  same  time,  the  remaining  behind  of  the 
development  of  the  sexual  glands  in  infantilism  is  only  a  subordinate  symp- 
tom of  the  entire  clinical  picture.  We  therefore  do  not  find  in  infantilism 
such  profound  developmental  disturbances  as  in  eunuchoidism.  The 
genitalia  are  quite  childish  and  the  sexual  glands  functionate  like  the  sexual 
glands  of  children,  while  in  eunuchoidism  the  sexual  glands  eventually  do 
not  functionate  at  all  or  slight  islands  of  the  sexual  gland  tissue  have 
developed  further,  corresponding  with  the  age,  whereby  there  occurs  an  en- 
tirely insufhcient  function,  a  function  that,  on  account  of  the  faulty  develop- 
ment of  the  accessory  apparatus,  is  lacking;  thus  we  see  that  the  sexual  glands 
of  infantilism  or  the  infantile  genitalia  are  essentially  different  from  those  of 
eunuchoidism. 

Thus  if  true  infantilism  comes  about  through  the  standing-still  of  the 
whole  organism  at  a  juvenile  stage  of  development,  the  ductless  glandular 
system  remains  just  a?  childish  as  the  skeleton  or  the  hematopoietic  apparatus 
or  the  central  nervous  system;  therefore  the  inhibition  of  the  ductless  glandu- 
lar system  is  only  coordinated  with  that  of  the  entire  organism;  as,  if  these 
premises  hold  good,  we  are  not  justified  in  classing  infantilism  with  the 
primary  ductless  glandular  diseases;  on  the  other  hand,  it  does  not  then  seem 
to  me  justifiable  to  designate  as  infantilism  sharply  delimited  clinical  pictures 
that  depend  on  a  primary  disease  or  developmental  disturbance  of  a  definite 
ductless  gland,  pictures  such  as  juvenile  myxedema,  juvenile  hypophysial 
dystrophy,  or  eunuchoidism. 

Before  I  enter  into  the  symptomatology  of  true  infantilism  and  the  basis 
of  the  view  just  expressed,  I  would  like  to  report  some  typical  cases  of  true 
infantilism. 

Observation  LVI. — J.  H.,  twenty  years  old.  At  the  age  of  seven  years,  commotio 
cerebri  through  fall  from  a  tree.  Present  manifestations  of  a  benign  pyloric  stenosis  with 
dilatation  of  the  stomach  and  hypersecretion.     For  one-half  year  tetany. 

Total  length,  142 3>^^  cm.;  lower  length,  69  cm.;  span  w'idth,  143  cm. 

The  patient  looks  like  a  boy  thirteen  years  old.  Facial  expression  and  psychical  at- 
titude entirely  childish.  Abundance  of  hair  on  head.  Beard  hair  absent,  hair  in  the 
axUlae  and  on  the  mons  Veneris  absent,  soft  downy  hair  on  face.  Penis  small.  Both 
testicles  small.  No  libido,  rarely  weak  erections  which  have  appeared  only  recently,  no 
ejaculations.  The  epiphysial  junctures  of  the  skeleton  of  the  hand  are  almost  all  still  open. 
For  two  years  tetany,  at  the  close  of  which  slight  manifestations  of  hyperthyrosis. 

Observation  LV II . — W.  K.,  eight  years  old.  Entrance  into  the  clinic  Nov.,  1910.  At 
the  age  of  four  years  gradual  deterioration  of  the  gait.  The  chUd  also  remained  backward 
mentally,  and  repeated  for  the  third  time  his  first  class  in  school. 

Typical  progressive  muscular  atrophy,  the  description  of  which  we  may  omit  here. 

Typical  length,  117  cm.  Circumference  of  head,  51  cm.  Circumference  of  breast,  57 
cm.  Circumference  of  abdomen,  55  cm.  From  coracoid  process  to  olecranon  25.5  cm. 
From  Uiac  spine  to  internal  malleolus  56  cm. 

Both  lobes  of  the  thyroid  distinctly  palpable. 

The  tongue  is  large,  always  is  seen  to  a  certain  extent  between  the  teeth.     Root  of 


470 


VEGETATRE    DISTURBANCES 


nose  not  retracted,  skin  everywhere  elastic,  feels  moist.  Cryptorchidism.  Pilocarpine 
o.oi  gm.  elicits  minimal  sweats,  minimal  salivation. 

o.ooi  gm.  adrenalin  shows  strong  action  on  the  pulse  and  on  the  blood-pressure,  distinct 
diuretic  action,  no  glycosuria. 

Leucocytes,  9400,  of  which: 

Neutrophiles,  55.1  per  cent. 

Large  mononuclears,  8.3  per  cent. 

Lymphocytes,  ^^.3  per  cent. 

Eosinophiles.  s-3  P^r  cent. 


^ 


te 


$ 


Fig.  82. — X-ray  picture  of  the  hand  in  true  infantilism  (Observation  LVD.     Delay  of  the 
closure  of  the  epiph\sial  junctures. 


From  Xov.  14  on,  one  thyroidin  tablet  a  day.  On  Dec.  iS,  o.ooi  gm.  adrenalin. 
Strong  action  on  the  pulse  and  blood-pressure;  now  1.43  gm.  sugar  in  the  urine. 

Under  the  intluence  of  the  thyroidin  medication  which  now  has  lasted  about  six  weeks, 
the  pulse  increases  hardly  at  all,  no  manifestations  of  intoxication. 

On  entrance  the  X-ray  examination  of  the  skeleton  of  the  hand  showed  the  following: 
The  distal  epiphysis  of  the  ulna,  which  should  be  deposited  normally  at  seventh  year,  is 
here  entirely  absent. 

The  bone  nuclei  of  the  skeleton  of  the  wrist  are  abnormallv  small. 


INFANTILISM 


471 


At  the  end  of  a  six  weeks'  thyroidin  medication  X-ray  examination  was  again  made, 
without  showing  any  change  worthy  of  mention. 

In  this  case  we  are  dealing  with  a  typical  progressive  muscular  atrophy, 
setting  in  early  and  associated  with  an  inhibition  of  development.  This  is 
both  physical  (abnormal  smallness,  cryptorchidism,  etc.)  and  mental.  The 
large  tongue  gives  rise  to  a  thought  of  myxedema,  but  on  careful  searching 
no  other  signs  of  myxedema  were  found.  Six 
weeks  of  the  thyroidin  medication  causes  no 
acceleration  of  ossification. 

Observation  LVIII. — R.  R.,  twenty  years  old. 
Entered  May,  191 2.  Several  cases  of  tuberculosis 
in  the  family.  The  girl  learned  to  walk  only  three 
years  ago.  Since  childhood  conjunctivitis  eczema- 
tosa.  From  youth  she  has  remained  behind  in 
growth  and  in  mental  development;  at  present  she 
has  the  psyche  of  an  eight-  to  ten-year-old  child. 
Although,  on  account  of  her  eyes,  she  never  went 
to  school,  she  can  read  and  write  and  takes  an  in- 
terest in  household  affairs. 

127  cm.  tall.  Span  width,  128  cm.  Lower  length 
(ant.    superior   spine   to    ext.   malleolus)   633^2    cm. 

Very  sparse  growth  of  hair  in  axillcc  and  on  the 
genitalia. 

Adenoids  in  nasopharyngeal  space.  Glands  of 
the  neck,  the  elbow,  and  the  groins  somewhat  en- 
larged. Slight  horizontal  furrowing  of  the  teeth. 
Since  sabre-sheath  form  of  the  bones,  but  otherwise 
no  signs  of  severe  rachitis. 

The  mammae  on  both  sides  developed  distinctly, 
little  glandular  substance  palpable.  First  menstrua- 
tion two  days  ago,  weak. 

Leucocytes,  7700,  of  which: 

Neutrophiles,  61  per  cent. 

Lymphocytes,  32  per  cent. 

Large  mononuclear,  5  per  cent. 

Eosinophiles,  2  per  cent. 

X-ray  examination.  Sella  turcica  normal,  no 
peribronchial  lymph  glands. 

Coarse  nystagmus  on  both  sides,  the  eye  grounds 
show  meduUated  nerve  fibers,  otherwise  they  are 
normal. 

X-ray  examination  of  the  skeleton  of  the  hand. 
The  ossification  corresponds  to  about  that  of  a  fif- 
teen- to  sixteen-year-old  individual. 

Observation  LIX. — B.  B.,  fourteen  years  old.  Entered  May,  191 2.  It  was  stated  that 
in  the  first  year  the  head  and  abdomen  were  very  large,  later  good  development,  could 
walk  at  two  years,  speak  at  three.  Remaining  behind  in  corporeal  development,  es- 
pecially since  the  first  year  of  life.     Mental  development  fairly  good.     Psyche  childish. 


Fig.  83. — Infantilism  in  progressive 
muscular  atrophy. 


472 


VEGETATIVE    DISTURBANCES 


Length  of  body,  m  cm.,  lower  length,  62  cm.,  span  breadth,  113.5  cm.,  length  of  arm, 
^8  cm. 

Slender,  weakly  child,  thin,  looks  like  a  child  eight  years  old.     Pallid.     The  head,  rela- 
tively large  (circumference,  54  cm.).     Frontal  protuberances  somewhat  prominent. 

Adenoid  vegetations  in  nasopharyngeal  space,  tonsils  enlarged;  in  the  neck,  in  the 
groins,  everyw^here,  are  palpable  glands  up  to  the  size  of  a  bean. 

Distinct  parallel  furrows  on  the  incisor  teeth  of  the  lower  jaw.     Slight  form  of  pectus 

carinatus.  Some  lordosis  of  the  lumbar  spine. 
Slight  affection  of  the  apices  of  the  lungs  on  both 
sides. 

Erythrocytes,  2,800,000, 
Hemoglobin,  60  per  cent. 
Leucocytes,  10,400,  of  which: 
Neutrophiles,  52.0  per  cent. 
Lymphocytes,  41. i  per  cent. 
Large  mononuclears,  2.5  per  cent. 
Eosinophiles,  4.0  per  cent. 
JNIast  cells,  0.5  per  cent. 

Slight  poikilocytosis.  X-ray  examination.  \'ault 
of  cranium  thin.  Sella  turcica  normal.  No  basis  for 
thymus-rest.  Right  divergent  strabismus,  both  pa- 
pillae somewhat  washed  out  and  pale,  otherwise  eye 
grounds  and  vision  normal. 

X-ray  examination  of  the  hand;  the  skeleton  of 
the  hand  about  corresponds  with  that  of  a  ten-year- 
old  boy. 

Symptomatology. — Ordinarily  the  dis- 
turbance in  growth  in  true  infantilism  is  very 
significant.  The  skeleton  shows  a  reten- 
tion of  the  childish  dimensions,  that  is  the 
lower  length  does  not  exceed  the  upper 
length,  or  exceeds  it  only  a  little.  The  head 
is  relatively  large,  the  bones  are  slender,  the 
navel  is  low,  the  pelvis  is  neither  mascuhne 
nor  feminine,  but  infantile.  The  occurrence 
of  the  bone-nuclei  and  the  closures  of  epiphy- 
ses are  delayed. 

The  genitalia  remain  at  a  child's  stage 
of  development,  they  have  the  size  and  di- 
mensions of  a  child's  genitalia;  we  are  not 
deahng  here  with  a  falling  away  of  the 
genital  function,  but  with  a  function  which 
corresponds  with  that  of  the  years  of  child- 
hood. Correspondingly  there  is  a  remaining  behind  of  the  secondary  sexual 
characters.     Also  the  vita  sexualis  is  that  of  a  child. 

The  lymphatic  apparatus  shows  deficient  involution.     We  find  there- 
fore commonly  a  relatively  great  count  of  lymphocytes  in  the  blood,  on 


Fig.  84. 


-Infantilism  (Observation 
LIX). 


INFANTILISM  473 

which  account  there  is  not  necessarily  present  a  status  lymphaticus,  al- 
though it  is  not  improbable  that  the  damaging  that  produces  the  infantilism 
also  often  leads  to  a  status  lymphaticus.  Moreover,  the  anemia  that  is  not 
rarely  found  in  infantihsm  can  be  regarded  as  a  direct  consequence  of  this 
deleterious  influence. 

The  hair  of  the  head  is  usually  abundant,  the  hair  on  the  trunk  is  usually 
absent,  but  not  always  entirely  absent.  The  hairiness  of  the  pubis  and  the 
perineum  is  usually  very  sparse  or  is  absent.  The  same  holds  good  for  the 
hair  in  the  axillse. 

The  internal  organs  are  as  a  rule  normal,  so  far  as  illnesses,  occurring  in 
early  years,  have  not  led  them  to  infantihsm.  The  vascular  system  seems 
in  the  most  cases  to  show  a  shght  grade  of  hypoplasia.  Also  the  blood- 
pressure  often  lies  on  the  lower  borders  of  the  normal. 

I  am  not  aware  as  to  the  existence  of  investigations  as  to  the  respira- 
tory metabohsm.  In  the  cases  that  I  investigated  the  tolerance  limits  for 
carbohydrates  approximate  the  normal.  Functional  testing  of  the  vegeta- 
tive nervous  system  sometimes  showed  slight  diminution  of  the  excitability. 
Not  much  importance  can  be  attached  to  this. 

Characteristic  for  true  infantihsm  is  the  retention  of  the  childish  features. 
We  find  the  childish  logic,  the  childish  instinct  for  imitating,  a  certain  anx- 
iety and  non-independence.  For  example  the  case  reported  by  me  (Observa- 
tion LVI),  acted  like  a  boy  when  at  his  visits  he  was  scolded  for  not  having 
collected  his  urine.  By  the  grown  people  of  the  clinic  he  was  treated  like 
a  child.  Ziehen  points  out  in  this  regard  that  in  infantilism  the  individual- 
izing association  characteristic  of  children  is  retained.  Also  the  psychical 
inhibitory  apparatus  is  only  deficiently  developed.  Di  Gaspero  attaches 
especial  value  to  the  retention  of  the  childish  ideas  of  value,  and  of  the  sug- 
gestibihty  of  children.  A  careful  description  of  the  psyche  of  infantihsm  is 
furnished  by  G.  Anton.  "The  mimicry,  gesticulations,  physiognomy,  cor- 
respond to  childish  age  phases,  as  do  the  pitch  and  the  modulation  of  the 
voice.  For  the  most  part  there  is  absent  the  childish  gaiety  and  freedom, 
often  there  comes  to  expression  feelings  of  insufficiency,  timidity,  and  peevish- 
ness." For  the  most  part  the  attention  may  be  readily  drawn,  but  is  readily 
deviable.  Constant  concentration  is  not  to  be  attained.  Comphcated  sense 
impressions  produce  a  feeling  of  unpleasantness.  "  Often  therefore  they  have 
acquired  a  routine  in  which  complicated  impressions  and  tasks  are  slipped 
by;  their  selection  tends  to  the  primitive,  the  simple."  I  have  attached 
value  to  reproducing  the  description  of  Anton,  because  it  is  enough  to  show 
that  the  psyche  of  persons  with  infantihsm  is  essentially  different  from  that 
of  eunuchoids. 

Forms. — According  to  the  intensity  of  the  noxious  agent  that  is  to 
blame  for  infantihsm,  do  different  forms  of  this  condition  occur,  from  the 
quite  excessive  forms  which  in  their  corporeal  and  mental  development 


474  VEGETAXrV'E    DISTURBANCES 

remain  little  children  all  their  lives,  to  the  poorly  pronounced  formes  frustes. 
Very  important  for  the  differentiation  of  the  forms  is  also  the  consideration 
of  the  phase  of  development  at  which  the  noxus  set  in.  "Every  age  period 
has  its  infantilism"  {di  Gaspero).  When  the  noxus  sets  in  relatively  late 
there  results  a  form  which  has  been  termed  "  juvenilism."  In  this  the  skele- 
ton is  no  longer  purely  childish.  The  genitalia  are  relatively  well  developed, 
etc.  We  find  very  commonly  the  juvenile  form  of  psychic  infantilism  in 
ordinary  life  {Anton).  According  to  whether  the  inhibition  of  develop- 
ment has  affected  the  more  the  skeleton,  the  psyche,  or  the  genitalia,  etc., 
we  may  speak  of  partial  infantilism.  An  instructive  example  of  a  juvenil- 
ism  furnished  by  a  case  briefly  reported  by  A  pert  and  Rouillard.  In  a 
thirty-eight-year-old  man  who  had  developed  normally  up  to  his  sixteenth 
year,  there  occurred  in  the  wake  of  a  typhoid  fever  a  remaining  behind  in 
corporeal  and  sexual  respects,  at  this  developmental  period.  There  were 
present  no  signs  of  eunuchoidism.  A  pert  and  Rouillard  attribute  this  in- 
hibition in  development  to  the  thyroid  gland.  As  no  signs  of  myxedema 
were  present,  I  would  dissent  from  this  view. 

The  excessive  form  of  infantilism  might  well  coincide  with  the  hypo- 
plastic dwarf  of  Breuss  and  Kolisko.  Breuss  and  Kolisko  indeed  state  that 
in  the  hypoplastic  dwarf  only  the  height  is  childish,  the  other  dimensions 
only  in  part  childish.  Probably  in  such  individuals  the  disturbance  has  its 
onset  in  fetal  life  or  in  early  youth. 

Etiology. — The  etiology  of  infantilism  is  very  manifold.  The  most 
divergent  toxic  and  infectious  deleterious  agents  are  blamed.  Alcoholism, 
saturnism,  nicotine-poisoning — agents  that  may  also  have  affected  the 
parents — further  malaria,  pellagra,  syphilis  (a  fine  example  is  furnished  by 
Peretz),  tuberculosis,  abdominal  tv^Dhoid  in  early  youth  (see  the  case  of 
A  pert  and  Rouillard);  polyserositis  (<;'.  Xeusser),  deficient  development  of  the 
cardiovascular  apparatus  {Hodhnoser  has  communicated  a  pronounced 
pertinent  case  that  was  only  125  cm.  tall  with  a  lower  length  of  66  cm.), 
and  further  cardiac  defects  acquired  in  early  youth  {Gilbert  and  Rathery) 
(and  in  this  nanisme  cardiaque  the  genital  disturbance  may  eventually  be- 
come less  pronounced),  and  the  traumata  that  may  affect  the  children  in  early 
youth  (the  case  J.  H.,  Observation  L\T,  suft'ered  a  commotio  cerebri  at  the 
age  of  seven  years).  Joffroy  described  two  cases  of  paralysis  generale  juvenile 
with  pronounced  infantilism.  I  have  reported  such  a  case  above  (see 
Observation  L\TI,  W),  further  it  has  been  supposed  that  unfavorable  condi- 
tions of  life,  and  conditions  of  nourishment  in  early  life  are  causal  factors, 
and  also  disturbances  of  nutrition,  chronic  diarrheas,  etc.,  existing  since 
early  fife  (see  later  concerning  pancreatic  infantilism).  The  position  of 
the  cases  with  hydrocephalus  does  not  seem  to  me  assured  as  yet,  in  these 
cases  consideration  must  be  given  especially  to  signs  of  hypophysial  in- 
sufficiency, especially  the  distribution  of  fat. 


INFANTILISM  475 

Also  the  liver  diseases  acquired  in  early  life  may  lead  to  infantilism. 
Lerehoullet  described  a  case  in  which  he  ascribed  hypertrophic  biliary  cirrhosis 
of  the  liver  as  the  cause  of  the  infantilism.  The  following  case  also  perhaps 
belongs  in  this  group. 

Observation  LX. — G.  A.,  twenty-one  years  old.  Entered  Nov.,  1909.  Since  early 
youth  strong  imbiber  of  alcoholic  liquors.  In  1906,  he  fell  in  the  water,  after  which 
pneumonia,  later  pleurisy.  Since  that  time  has  not  grown  much.  For  about  two 
years,  swelling  of  the  abdomen,  edema  of  the  legs,  and  enlargement  of  the  liver.  The 
ascites  subsided,  the  liver  remained  large  and  painful. 

According  to  his  statement,  for  about  three  years  after  the  time  of  puberty  the  patient 
had  libido  and  erections,  that  later  ceased.     Never  pollutions,  never  cohabitation. 

Very  considerably  enlarged  liver,  painful  to  pressure,  pole  of  the  spleen  palpable, 
heart  dullness  somewhat  enlarged  to  left  and  to  the  right.  Extra-systoles,  no  ascites, 
no  albumin. 

The  physiognomy  is  juvenile,  no  beard,  no  axillary  hair,  sparse  growth  on  mons  Ven- 
eris.    Testicles  and  penis  of  normal  size. 

Differential  Diagnosis. — If  we  confine  ourselves  to  the  symptoms  just 
described,  the  delimitation  of  true  infantilism  from  the  diseases  of  the  ductless 
glands  associated  with  infantile  features  is  not  difficult. 

And  yet  on  closer  examination  of  the  individual  cases  described  under  the 
same  infantilism  we  find  that  very  frequently  later  authors  confuse  in- 
fantilism with  diseases  of  the  ductless  glands.  Thus  I  would  hold  that  in  the 
communication  of  Richon  and  Jeandelize  the  first  of  the  cases  described  was 
probably  an  eunuchoid,  the  second  a  cretinoid,  and  the  third  perhaps  a 
true  case  of  infantilism.  Another  example:  In  the  communication  of  E. 
Levi,  I  regard  the  first  case  as  one  of  hypophysial  dystrophy,  the  second  is 
difficult  to  classify,  the  third  is  perhaps  a  typical  case  of  true  infantilism. 

I  would  detail  somewhat  more  exactly  the  most  important  differential 
diagnostic  features: 

Let  us  begin  with  the  delimitation  from  infantile  myxedema.  In  the 
French  school  two  types  of  infantilism  are  distinguished,  the  Lorain  s  type, 
which  on  the  whole  is  true  infantilism,  and  second,  myxinfantilism.  A\Tien 
however  we  go  back  to  Brissaud's  original  publication,  we  find  that  the  char- 
acterization of  myxinfantilism  is  very  inexact.  Here  begins  an  error  that 
has  continued  until  the  present  and  that  may  be  regarded  as  the  chief 
cause  of  the  prevailing  confusion.  Brissaud  describes  myxinfantilism  in  the 
following  manner:  The  face  is  round,  the  lips  are  thick,  the  nose  small,  the 
cheeks  are  thick,  the  genitalia  infantile,  the  thyroid  gland  small,  the  ossifica- 
tion is  delayed,  dentition  is  retarded  or  fails,  the  neck  is  short,  and  there 
often  exists  lordosis  of  the  lumbar  spine ;  among  the  individuals  belonging  to 
this  type  there  are  also  those  whose  health  may  be  very  good.  Brissaud  held 
the  opinion  that  in  the  majority  of  cases  myxinfantilism  is  not  an  etat  morbide 
and  he  refers  also  partial  infantilism  to  an  insufficiency  of  the  thyroid 
gland.     As  an  example  he  quotes  the  cases  of  two  sisters  of  whom  the 


476  VEGETATR'E    DISTURBANCES 

elder  looked  to  be  about  three  years  younger  than  the  other  and  showed 
an  entirely  childish  habitus.  He  also  quotes  the  case  of  a  boy  of  sixteen 
years,  who  looked  as  if  he  were  eleven  years  old,  and  whose  psychical  attri- 
butes corresponded  with  that  of  the  latter  age.  At  the  age  of  ten  years  of  life 
he  had  sustained  an  inflammation  of  the  throat  and  a  swelling  of  all  lymph 
glands;  Brissaud  here  regards  it  as  established  that  at  that  time  the  thyroid 
gland  was  affected.  The  third  case  that  Brissaud  cites  is,  on  account  of  the 
inaccurate  description,  hard  to  classify.  I  need  hardly  detail  more  intimately 
that  the  belonging  of  the  cases  cited  to  infantile  myxedema  is  at  least  un- 
certain, even  unlikely.  A  priori  we  may  withdraw  from  consideration,  how- 
ever, the  classilication  on  the  etiological  basis,  according  to  Brissaud' s  assump- 
tion that  a  severe  disturbance  of  development  could  depend  on  a  thyroid 
insufficiency  without  other  symptoms  of  myxedema  being  present.  The  in- 
hibition of  ossification  alone,  on  which  some  stress  has  been  laid,  is  no  certain 
sign  of  thyroid  insufficiency.  Meige  and  Allard  point  out,  it  is  true,  as  the 
foundation  of  this  assumption,  a  case  of  typical  Lorain's  infantilism  in  which 
ossification  had  advanced  much  further  than  in  a  case  of  myxinfantilism. 
E.  Levi  showed,  however,  that  in  the  type  Lorain  the  ossification  is  much  de- 
layed as  compared  with  that  of  a  normal  individual  of  this  age.  It  is  certain 
that  also  in  true  infantilism  there  exists  a  certain  inhibition  of  ossification, 
and  that  even  a  certain  acceleration  of  ossification  may  follow  thyroid  gland 
therapy.  But  this  does  not  furnish  a  certain  demonstration  of  the  thyrogenic 
pathogenesis  of  such  cases,  for,  asFerranini  already  mentions,  the  stimulation 
of  the  metabolism  through  the  administration  of  the  thyroid  gland  may  help 
somewhat.  To-day,  when  the  manifestations  of  thyroid  gland  insufficiency 
in  childhood  are  so  carefully  studied,  we  would  require  unconditionally  sure 
signs  of  childish  myxedema  if  we  were  to  call  a  case  myxinfantilism.  The 
delimitation  of  true  infantilism  from  severe  forms  of  childish  myxedema  is 
indeed  readily  made.  The  mitigated  forms  may  be  distinguished  from  it  by 
the  presence  of  myxedematous  alterations  of  the  skin,  thickening  of  the 
tongue  and  lips,  the  umbilical  hernia,  disturbances  of  intelligence,  apathy,  and 
especially  the  result  of  thyroid  gland  therapy. 

Naturally  there  also  occur  mixed  cases.  Signs  of  thyroid  gland  insuf- 
ficiency may  be  added  to  those  of  true  infantilism,  temporarily  or  perma- 
nently. Perhaps  such  a  case  is  described  by  Duprc  and  Pagniez.  Here  a 
myxedema  began  at  the  fifteenth  year  of  life  in  a  case  of  true  infantilism. 

Again,  the  delimitation  of  true  infantilism  from  eunuchoidism  is  not  diffi- 
cult in  most  cases.  It  is  quite  unintelligible  how  Peritz  can  regard  eunuchoid- 
ism as  the  purest  form  of  infantilism.  In  eunuchoidism  we  have  an  isolated 
severe  disturbance  of  the  development  of  the  sexual  glands,  and  here  the 
analogy  with  eunuchoidism  ends,  the  dimensioning  of  the  body  [in  eunu- 
choidism] has  nothing  in  common  with  the  childish  dimensions.  (There  is 
significant  predominance  of  the  length  of  the  extremities  and  small  head 


INFANTILISM 


477 


[in  eunuchoidism].)  Also  the  psyche  of  typical  eunuchoids  is  not  childish 
throughout.  The  feeling  of  absent  virility  here  often  leads  to  timidity  and 
eventually  to  deep  mental  depression,  while  the  childish  features  [of  the  dis- 
ease] are  absent.  Wolf,  just  as  has  Peritz,  has  spoken  against  the  designation 
eunuchoid,  with  incorrectness.  Of  the  four  cases  that  Woljf  communicates, 
case  3  probably  belongs  to  true  dwarfism,  associated  with  genital  disturbance 
(Paltaufs  type).  He  is  certainly  not  an  eunuchoid,  but  a  mixed  form  be- 
tween true  dwarfism  and  infantilism.  The  other  three  cases  are  however 
typical  infantilism,  distinguished  from  true  eunu- 
choids by  their  childish  psyche  and  by  the  pro- 
portioning of  their  bodies. 

The  delimitation  of  true  infantilism  from 
typical  juvenile  hypophysial  dystrophy  is  easy. 
In  this  too  is  found  the  disturbance  in  growth, 
but  to  the  disturbance  is  added  the  typical  dis- 
tribution of  fat,  and  the  disturbance  of  develop- 
ment of  the  genitalia  is  much  more  severe  and  is 
eventually  retrogressive.  There  are  also  present 
symptoms  of  increased  intracranial  pressure.  I 
would  here  point  out,  as  I  have  already  in  the 
chapter  on  the  hypophysis,  that  it  is  quite  un- 
justifiable to  refer  off-hand  to  the  hypophysis  a 
disturbance  of  growth,  if  other  manifestations  of 
hypophysial  insufficiency  are  not  otherwise  pres- 
ent. Aschner  has  described  a  sixteen-year-old 
dwarf  girl,  132  cm.  tall;  the  ossification  and  den- 
tition were  delayed,  her  proportions  were  childish, 
and  psychically  and  intellectually  she  was  child- 
ish. She  became  pregnant  in  consequence  of  a 
rape.  This  indeed  does  not  speak  much  against 
existing  infantilism  of  the  genitalia,  as  under  cir- 
cumstances children  may  become  pregnant  before 
the  onset  of  menstruation.  Aschner  rejects  the 
expression  infantilism  as  indefinite,  and  regards 
the  cause  of  the  disturbance  of  growth  as  hypo- 
physial without  furnishing  any  evidence  for  his 
opinion.  I  regard  this  case  as  true  infantilism  or 
as  a  hypoplastic  dwarf. 

Naturally  there  are  numerous  cases  that  con- 
stitute transitional  cases  between  true  infantilism  and  the  hypophysial  or 
eunuchoid  form  of  dystrophia  adiposo-genitalis.  As  example  I  cite  the 
following: 

Observation  LXI . — B.  A.,  sixteen  years  old;  entered  the  clinic  February,  191 1.     Father 


Fig.  85. — Mixed  form  between 
true  infantihsm  and  dystrophia 
adiposo-genitalis. 


478  VEGETATRE    DISTURBANCES 

dead.  ]\Ioher  had  had  lues  before  the  child's  birth.  Wassermann  reaction  is  still  posi- 
tive. The  boy,  too,  gives  a  positive  Wassermann.  The  boy  learned  to  speak  and  walk  as 
late  as  three  years  old.  At  the  age  of  eight,  a  fall  from  a  second  story.  Unconsciousness 
for  ten  minutes,  and,  according  to  statements,  no  after  effects. 

The  boy  is  small,  length  of  body  142.5  cm.  Lower  length  82^2  cm.  Psyche 
childish,  corresponding  to  that  of  a  boy  thirteen  years  old. 

Slight  sinking-in  of  the  bridge  of  the  nose:  Hutcliiiison's  teeth.  No  hair  at  all  in  the 
axilla  and  on  the  pubis.  On  the  breasts  slight  collections  of  fat,  collection  of  fat  on  the 
mens  Veneris.     Penis  very  small,  testicle  small,  in  the  scrotum  on  both  sides. 

Scoliosis  of  the  thoracic  spine  to  the  left;  left  pupil  twice  the  size  of  the  right;  both  fail 
to  react  to  light,  patellar  and  Achilles  reflexes  very  lively.  Hyperesthesia  of  the  whole  left 
side  of  the  body,  sharply  cut  off  at  the  median  line.  No  other  nervous  condition  found. 
Fundus  normal;  to  X-ray  examination  sella  turcica  normal. 

The  epiphysial  joints  of  the  hand-skeleton  are  wide  open,  and  the  sesamoid  bones  as  yet 
show  no  bone-nuclei. 

Diagnosis. — Infantilism  -f  dystrophia  of  adiposo-genitalis  of  a  slight  grade,  in  heredi- 
tary lues. 

In  this  case  of  hereditary  lues  the  excess  of  the  lower  length  over  the  upper 
length  militates  against  pure  infantilism.  Further,  the  eunuchoid  distri- 
bution of  fat  is  plainly  indicated.  The  developmental  disturbance  of 
the  sexual  glands  is  somewhat  more  pronounced,  and  is  perhaps  of  hypophysial 
origin  (congenital  lues,  different  symptoms  on  the  part  of  the  nervous 
system) ;  on  the  other  hand  these  symptoms  are  slight  in  comparison  with 
the  inhibition  of  growth,  and  the  psyche  is  decisively  childish. 

Just  a  few  words  concerning  the  so-called  pancreatic  infantilism.  Bram- 
well  and  later  Rentoul  have  described  such  cases.  In  the  case  of  Rcntoul 
we  are  dealing  with  a  girl  eighteen  years  old,  who  from  youth,  suffered  with 
diarrheas  (fat  stools?).  She  grew  slowly  up  to  the  eleventh  year,  and  then, 
with  regard  to  growth,  remained  at  a  standstill  to  the  age  of  eighteen.  She 
looked  like  an  eight-year-old  girl.  The  stools  improved  very  much  on  the 
administration  of  pancreatin;  she  now  increased  rapidly  in  weight  and  grew  in 
four  months  about  2  in.  I  do  not  regard  as  appropriate  the  term  "pancre- 
atic infantilism."  Thereby  we  might  be  induced  to  attribute  infantilism  to  a 
disturbance  of  the  internal  secretion  of  the  pancreas,  although  in  these 
cases  we  may  be  dealing  with  true  infantilism  brought  about  through 
nutritional  disturbances.  WTien  the  nutritional  disturbance  improves,  the 
retardation  of  the  development  may  in  part  be  mitigated.  Disturbance 
of  the  internal  secretion  of  the  pancreas  does  not  lead  as  far  as  is  known 
to  infantilism.  Youthful  diabetics  do  not  show  infantile  features.  In  several 
cases  of  juvenile  diabetes  I  have  convinced  myself  that  ossification  does 
not  remain  behind. 

The  vegetational  disturbances  in  early  childhood  through  damaging  of 
the  suprarenal  cortex  are  as  yet  too  little  investigated  that  we  can  delimit 
them  from  infantilism.  I  refer  to  the  chapter  on  this  subject.  Apparently 
hypoplasia  of  the  chromaffin  tissue  likewise  does  not  lead  to  true  infantilism. 


INFANTILISM  479 

Probably  such  cases  belong  to  the  so-called  hypoplastics  of  Bartels  or  to 
true  status  lymphaticus. 

Pathogenesis. — As  I  already  mentioned  at  the  beginning,  the  tendency 
is  coming  more  and  more  to  the  fore  to  regard  the  cause  of  infantilism  as  a 
disturbance  of  the  ductless  glands,  or  as  a  disturbance  of  ductless  gland- 
ular correlations;  the  disturbances  of  the  correlations  is  a  favorite  modern 
catchword.  This  opinion  I  cannot  share.  I  regard  true  infantilism  as  the 
vegetative  disturbance  dependent  on  an  inhibition  of  development  of  the 
whole  organism.  But  the  developmental  retardation  of  the  ductless 
glands  is  coordinated  with  that  of  the  entire  organism.  Hence  there  is 
found  no  disturbance  of  correlation  among  the  ductless  glands,  but  a  func- 
tion of  them  graduated  for  an  organism  that  remains  childish,  a  function 
fully  suited  for  the  childish  conditions.  In  true  infantilism,  also  the  sexual 
glands  functionate — for  signs  of  eunuchoidism  are  absent — but  they  function- 
ate like  those  of  children.  According  as  the  damage  has  occurred  in  the 
fetal,  the  infantile,  or  the  juvenile  organism,  do  there  occur  fetalism,  in- 
fantilism, or  juvenilism. 

A  damaging  that  in  youth  acts  electively  on  the  ductless  glandular  system, 
and  injures  it  severely  must,  according  to  my  view,  lead  to  a  vegetational 
disturbance  that  is  similar  to  multiple  ductless  glandular  sclerosis.  It 
would  condition  cachexia  and  premature  senility,  but  not  infantilism. 

The  conception  of  infantilism  agrees  with  that  of  Anton,  who  rules  out 
dystrophic  infantilism  from  the  true  ductless  glandular  diseases.  The 
difference  consists  only  in  the  fact  that  I  limit  the  idea  of  infantilism  still 
more  and  do  not  class  with  it  the  true  ductless  glandular  diseases  of  childhood. 

I  need  hardly  mention  again  that  this  view  holds  only  for  the  typical 
forms  of  infantilism.  There  are  perhaps  as  many  transitional  forms  as 
typical  forms  that  pass  over  into  the  ductless  glandular  diseases.  These 
transitional  forms  may  exist  between  infantilism  and  various  other  diseases — 
hypophysial  or  eunuchoid  dystrophia  adiposo-genitalis,  or  pronounced 
status  lymphaticus,  with  marked  hypoplasia  of  the  chromaffin  tissue,  or 
true  myxedema  or  cretinism,  or  other  vegetative  disturbances  yet  to  be 
described  (true  dwarfism,  mongolism,  etc.).  I  believe  it  is  better  to  be  pre- 
cise in  the  delimitation  of  true  infantilism  as  in  this  way  the  transitory  forms 
that  are  so  frequent,  are  made  easier  to  recognize  and  easier  to  analyze. 

Prognosis. — The  later  fate  of  true  infantilism  has  not  as  yet  been  thor- 
oughly studied.  It  is  known,  however,  that  the  patients  show  an  especial 
disposition  for  various  diseases  and  mostly  die  prematurely  {di  Gasper o, 
W.  A .  Freund,  Hegar,  et  al.) .  Especially  does  tuberculosis  reap  a  rich  harvest 
among  them.  Also  their  mentality  seems  to  suffer  under  the  roughjn- 
fiuences  of  life  and  its  severe  conflicts. 

Treatment. — The  treatment  in  the  true  forms  as  yet  is  almost  hopeless. 
Thyroid  gland  medication,  hypophysis  medication,  etc.,  may  yield  slight  re- 


480  VEGETATIVE    DISTURBANCES 

suits  in  the  mixed  forms.     True  infantilism  usually  shows  a  lower  tolerance 
for  thyroid  preparations. 

II.     TRUE  DWARFISM 

True  dwarfism  as  a  proportioned  nanism  may  be  rather  well  delimited 
from  the  other  vegetative  disturbances  that  I  have  thus  far  described  or 
will  hereafter  describe  in  this  chapter;  as  all  of  these  with  the  exception  of 
true  infantilism  are  disproportioned  nanisms,  while  in  true  infantilism  the 
childish  dimensions  are  retained.  In  spite  of  the  fact  that  we  are  consider- 
ing true  dwarfism  in  this  connection,  it  constitutes  no  uniform  affection.  In- 
deed attempts  have  been  made  to  distinguish  two  different  types  of  true 
dwarfism  that  differ  from  each  other  in  important  points  and  perhaps  are 
also  to  be  separated  etiologically.  There  exists,  however,  as  we  shall  see, 
all  possible  transitions  between  these  types.  As  long  as  we  do  not  know 
anything  certain  concerning  the  etiology  of  true  dwarfism  a  satisfactory 
terminology  for  all  the  cases  that  belong  in  this  group  is  not  possible. 

Historical. — In  this  short  exposition  I  would  not  enter  into  the  de- 
scriptions that  exist  in  the  old  literature.  It  is  to  be  supposed  that  among  the 
numerous  dwarfs  that  in  former  times  were  retained  at  the  courts  of  no- 
bility on  account  of  curiosity  or  that  were  exhibited  in  the  show  booths 
[as  freaks]  there  were  some  that  were  true  dwarfs.  The  descriptions  of 
these  are,  how^ever,  very  inexact.  Therefore  I  shall  limit  myself  to  the 
fewer  and  more  careful  communications  in  the  later  literature.  The  first 
exact  description  of  the  skeleton  of  a  true  dwarf  originates  with  A.  Paltaiif 
in  the  year  1891,  while  v.  Hansemann  was  the  first  to  separate  the  two 
types  of  true  dwarfism,  v.  Hansemann  distinguished  a  nanosomia  pri- 
mordalis  and  a  nanosomia  infantalis.  In  the  latter  at  the  time  of  birth  the 
individual  is  of  normal  size.  Growth  ceases  only  later,  the  epiphysial  junc- 
tures remaining  open;  often  the  individual  remains  infantile.  This  form  is 
identical  with  that  described  by  Paltauf.  The  primordial  dwarf  is  small 
from  the  beginning,  although  his  development,  apart  from  the  smallness, 
proceeds  in  the  normal  manner.  He  is,  therefore,  a  veritable  diminutive 
human  being;  Sainton  and  Launois  distinguish  this  true  dwarfism  from  the 
other  vegetative  disturbances,  without,  however,  considering  the  other  type. 
Also  E.  Levi  who  has  published  a  thorough  study  of  this  form  of  dwarfism, 
has  considered  Paltauf  s  form  insufficiently. 

A.  The  Primordial  Nanosomia. — An  excellent  example  of  this  form  is 
the  case  described  by  Virchow  and  later  by  x'.  Hansemann.  It  was  that  of 
an  individual  twenty-two  years  old  (who  at  the  age  of  eleven  years  was 
investigated  by  Virchow)  who  was  114  cm.  lull.  He  was  entirely  well  pro- 
portioned, the  intelligence  was  well  developed,  the  genitalia  were  well  de- 
veloped, except  that  cryptorchidism  was  present.  The  epiphysial  junctures 
had  ossified.     At  birth  he  had  weighed  only  500  gm.     This  was  doubted 


TRUE    DWARFISM  48 1 

by  V.  Hansemann  although  it  is  certain  that  at  the  birth  the  parents  were 
impressed  with  the  abnormal  smallness.  He  was  the  fifth  child  of  twelve, 
and  the  first  dwarf.  Later  three  dwarf  children  followed,  but  they  did  not 
attain  a  high  age.  Between  them  there  were  births  of  normal-sized  children, 
that  later  also  developed  normally. 

To  the  primordial  dwarfs  belong  also  the  dwarf  family  ^lagri.  studied  by 
various  Italian  authors  and  exactly  described  by  Taruffi.  The  husband  and 
wife  Magri  were  entirely  normally  developed;  of  thirteen  children  eight 
survived,  five  were  of  entirely  normal  size,  three  extraordinarily  small.  Of 
these  there  was  a  girl  102  cm.  tall,  in  whom  menstruation  occurred  late  but 
who  was  other-^dse  normal.  A  boy  of  no  cm.  of  bright  temperament,  but 
bad  character,  married  in  his  twenty-sixth  year  a  woman  of  normal  size  and 
had  by  her  two  children — a  boy  who  was  of  normal  size  and  a  girl  who  was 
apparently  a  dwarf.  The  third  dwarf  child  of  the  ]\Iagri  husband  and  vdie 
was  109  cm.  tall.     All  three  ]\Iagris  grew  taller  very  slowly. 

Very  exactly  studied  are  also  the  cases  of  Levi.  These  I  shall  now  de- 
scribe more  in  detail.  The  first  was  a  forty-nine-year-old  man,  109  cm. 
tall.  The  lower  length  was  shorter, than  the  upper  length.  The  indi^^[dual 
was  small  already  at  birth;  the  genitalia,  the  secondary  sexual  characters, 
and  the  intelligence  developed  fully.  At  the  age  of  twenty,  he  married  a 
woman  of  normal  size,  who  after  eight  years  bore  a  child  of  extraordinary 
smallness.  Two  years  later  there  followed  a  still  smaller  child,  who  died  at 
the  age  of  ten  years.  At  the  age  of  forty-nine  years  the  man  was  still 
sexually  active.  The  second  case  of  Levi  was  that  of  a  twelve  and  one- 
half-year-old  son  of  case  I.  He  was  77  cm.  tall,  and  very  intelligent.  The 
third  case  was  that  of  a  thirty-three-year-old  man.  in  cm.  tall,  weighing 
25  kg.  The  lower  length  was  64  cm.;  the  father  was  very  small,  the  mother 
of  normal  size.  The  stunting  of  growth  became  prominent  especially 
between  the  eighth  and  the  tenth  year.  At  the  age  of  twenty-eight  he 
married,  and  his  child  at  two  years  old  of  extraordinary  diminutiveness. 
In  all  cases  the  ossification  and  the  closure  of  the  epiphyses  corresponded  to 
the  age.  Levi  also  emphasizes  the  fact  that  these  cases,  fike  the  dwarf 
described  by  v.  Hansemann,  showed  a  slight  retraction  of  the  bridge  of  the 
nose  and  a  slight  degree  of  drum-stick  fingers. 

The  primordial  dwarf  is  hence  characterized  by  the  fact  that  the  dwarfism 
exists  already  at  birth,  that  apart  from  the  smallness  the  development  pro- 
ceeds normally,  and  that  the  genitalia,  the  ossification  and  the  epiphysial 
junctures,  and  the  intelligence  develop  rather  normally.  According  to 
Hansemann  "infantile"  features  are  found  only  here  and  there,  for  example, 
cryptorchidism,  or  in  the  case  of  v.  Hansemann  enlarged  thymus,  or  retention 
of  the  lobules  of  the  kidney,  abnormal  length  of  mesocolon,  funnel-shaped 
proximal  end  of  the  appendix,  etc.  Levi  points  out  the  slight  retraction  of 
the  root  of  the  nose  and  the  sHght  degree  of  drum-stick  fingers. 


482  VEGETATR'E    DISTURBANXES 

B.  Paltaufs  Dwarf. — A .  Paltauf  described  the  skeleton  of  a  dwart  who  died 
at  the  age  of  forty-nine  years;  all  the  epiphyses  were  open.  The  individual 
was  1 1 2.5  cm.  tall;  he  came  from  an  entirely  normal  family;  the  intelli- 
gence was  normal  (he  had  taken  part  in  two  campaigns).  He  had  twenty- 
eight  erupted  teeth;  the  thyroid  gland  was  normal.  -1.  Pa//a 2// believes  that 
in  this  case  he  was  dealing  with  a  nanosomia  sui  generis  that  depended 
on  an  earlier  stage  of  the  formation-age  on  account  of  the  bones  remain- 
ing at  a  standstill  in  development.  Also  the  deformed  cartilaginous  base 
of  the  skull  had  ceased  its  growth,  while  the  bones  laid  down  in  mem- 
brane grew  further,  thus  allowing  the  normal  development  of  the  brain; 
although  a  slight  cretinoid  facial  expression  was  thereby  brought  about. 
The  skeleton  is  proportioned,  but  shows  childish  dimensions,  the  upper 
and  lower  lengths  approximating  those  of  a  child  (Breus  and  Kolisko). 
Such  individuals  may  suddenly  begin  to  grow  again.  A.  Paltauf  cites  two 
instances,  the  English  dwarf  Jeflery,  who  began  to  grow  again  at  the  age  of 
thirty  years,  and  the  Polish  dwarf  Borwilawski.  The  brothers  and  sisters 
of  the  latter  were  also  dwarfish,  but  his  children  developed  perfectly  normal. 
I  shall  limit  myself  to  the  citation  of  the  well-observed  cases. 

The  case  of  Schaafhausen  was  a  sixty-one-year-old  man.  94  cm.  tall; 
several  members  of  the  family  were  also  dwarfish,  the  genitalia  were  infantile, 
the  facial  expression  childish.  The  sutures  of  the  skull  were  all  ununited,  the 
epiphyses  nearly  all.  The  observations  of  Schauta,  Ranke,  and  von  Voit 
perhaps  belong  here  also.^  Hitschmann  describes  a  thirty-live-year-old  man 
who  came  of  normal  family  and  who  developed  normally  up  to  the  age  of 
five  years.  Then  growth  was  retarded,  although  up  to  the  twenty-fifth  and 
twenty-sixth  years  he  did  grow  somewhat.  He  was  108  cm.  tall,  beardless, 
the  voice  did  not  change,  the  thyroid  gland  was  normal.  X-ray  examination 
showed  epiphysial  junctures  open  I'^o  cm-  the  intelligence  was  normal.  He 
was  an  actor  with  a  Lilliputian  troup. 

A  second  case  of  Hitschmann  was  that  of  a  twenty-two  and  one-half- 
year-old  singer;  the  inhibition  of  growth  began  at  the  tenth  year.  She  was 
125  cm.  tall,  slender,  the  intelligence  was  normal,  the  epiphyses  were  for 
the  most  part  ununited. 

Joachimsthal  describes  several  members  of  a  Lilliputian  troup,  among 
whom  was  an  individual  thirty  years  old,  in  whom  the  stunting  of  growth  had 
begun  in  the  third  year;  at  fifteen  years  of  age,  she  was  90  cm.  tall,  and  at 
thirty  years  100  cm.  tall.  The  facial  expression  was  childish,  the  voice  had 
not  changed  and  the  axillary  hair  was  absent.  All  epiphysial  junctures 
wTre  open.  The  bone  nuclei  were  about  as  well  developed  as  those  of  a  ten- 
year-old  child.  In  an  individual  thirty-six  years  old  the  inhibition  had 
begun  at  the  age  of  seven.     At  the  age  of  twenty-two  he  was  105  cm.  tall, 

'  The  case  of  His,  quoted  by  PallauJ,  belongs  to  the  endemic  cretins,  that  of  Dalcga  to  the  spor- 
adic cretins. 


TRUE    DWARFISM  483 

and  at  the  age  of  thirty-six,  128  cm.  taU,  the  epiphysial  junctures  were  open, 
the  bone  nuclei  had  developed  further.  In  an  individual  thirty-three  years 
old  the  inhibition  had  begun  at  the  age  of  ten  years,  at  twenty  years  he  was 
109  cm.  tall,  at  thirty-three  years  134  cm.  tall;  in  a  woman  thirty  years  old 
the  inhibition  had  begun  at  the  age  of  eight  years,  at  nineteen  years  she 
was  103  cm.  tall,  now  132  cm.  tall.  To  the  Paltaufs  type  belongs  probably 
the  celebrated  dwarf  Helen  Gubler  called  the  "Puppenfee"  [doll  fairy].  At 
birth  she  was  normal.  She  ceased  growing  at  the  age  of  six  years,  and  at 
twenty  years  was  106  cm.  tall. 

If  we  survey  the  cases  quoted,  we  find  that  the  Paltaufs  type  may  be 
characterized  thus:  At  birth  the  individuals  are  of  normal  size,  and  at  first 
show  a  normal  development.  Only  later,  hut  at  all  events  mostly  in  early  youth, 
they  suddenly  cease  growing.  The  epiphysial  junctures  remain  open,  and 
in  all  cases  there  occurs  a  quite  slow  further  growth,  the  inhibition  being 
broken  through  in  exceptional  cases  only.  The  development  of  the  bone 
nuclei  is  in  nearly  all  cases  delayed  only  a  little,  the  development  of  the 
intelligence  is  normal.  On  the  contrary  the  genitalia  and  the  secondary 
sexual  characters  remain  behind  almost  always.  The  cause  of  this  growth 
disturbance  is  as  yet  not  known. 

The  typical  Paltaufs  dwarf  differs  essentially  from  an  individual  with  true 
infantihsm.  In  the  latter  condition  not  all  the  epiphysial  junctures  remain 
open,  but  the  ossification  is  highly  retarded,  so  that  we  find  ununited  only 
those  junctures  that  tend  to  close  the  latest  otherwise.  Then  too  the 
psyche  of  Paltaufs  dwarf  is  ordinarily  not  childish.  I  have  therefore  dis- 
carded V.  Hansemann's  expression  ''infantile  dwarf"  and  have  chosen  the 
expression  "Paltaufs  type." 

The  distinction  between  the  primordial  dwarf  and  Paltaufs  dwarf,  on 
the  one  hand,  and  high-grade  infantihsm  on  the  other  hand  serves  only  for 
the  typical  cases.  It  will  readily  be  seen  that  transitional  forms  between  the 
two  varieties  of  dwarf  and  true  infantilism  occur.  To  quote  some  examples: 
Joachimsthal  describes  among  his  cases  two  thirty-six-year-old  individ- 
uals of  114  cm.  and  116  cm.  heights  respectively.  With  these,  growth 
has  remained  at  a  standstill  at  about  the  tenth  year.  We  can  therefore  not 
classify  them  with  the  primordial  dwarfs.  The  epiphysial  junctures  were, 
however,  closed,  and  both  menstruated  regularly  since  their  twentieth  year. 
In  a  female  dwarf  with  retained  epiphysial  cartilages  the  sexual  organs  were 
developed  quite  normally.  She  conceived,  and  at  Cesarean  section  was 
delivered  of  a  child  above  the  normal  in  weight  and  size. 

The  circumstance  that  there  are  transitions  between  the  primordial  and 
the  Paltaufs  type  does  not  mean  that  they  both  rest  on  the  same  etiological 
basis.  It  would  be  very  easy  to  assume  that  in  the  primordial  dw^arf  the 
noxus  took  its  effect  in  fetal  Hfe,  in  Paltaufs  dwarf,  in  postfetal  life.  This 
does  not,  however,  explain  the  great  difference  in  the  relation  of  the  genitalia. 


484  VEGETATIVE    DISTURBANCES 

As  will  be  seen  by  the  example  quoted,  the  familial  hereditary  occurrence  is 
common  to  both  types.  In  both  types,  too,  the  children  of  the  person  affected 
may  develop  normally. 

There  therefore  does  not  seem  to  me  to  lie  at  hand  any  basis  for  con- 
sidering true  dwarfism  as  an  affection  of  the  ductless  glandular  system.  I 
need  hardly  point  out  that  there  is  no  involvement  of  the  thyroid  gland. 
Aschner  would  indeed  make  the  hypophysis  answerable  for  dwarfism — cer- 
tainly incorrectly — for  all  the  symptoms  characteristic  of  hypophysial 
dystrophy  are  absent. 

III.  THE  RACHITIC  DWARF 

Dwarfism  may  be  the  result  of  a  high-grade  rachitis  developing  in 
children.  According  to  Breus  and  Kolisko,  in  addition  to  the  inhibition  of 
growth  in  height,  there  are  found  regularly  also  curvatures — under  circum- 
stances the  bones  are  weak  and  flexible.  "The  disturbance  of  the  periosteal 
ossification,  in  contradistinction  of  endochondral  ossification,  comes  into  the 
foreground."  Breus  and  Kolisko  also  state  that  in  such  cases  the  epiphysial 
junctures  can  often  remain  ununited;  Gulecke,  however,  reports  three  cases 
of  dwarfism  who  had  suffered  severe  rachitis  in  early  life  and  yet  showed  on 
X-ray  examination  premature  synostosis  of  the  epiphysial  junctures.  Gulecke 
assumes  that  the  epiphysial  cartilages  were  severely  damaged  by  the  rachitis, 
and  that  then  reparatory  processes  set  in  which  led  to  premature  ossification. 
In  fresh  cases  the  X-rays  show  washing  out  of  the  boundaries  between  the 
bone  nuclei  and  cartilage,  and  at  the  site  of  the  epiphyses  broad  light  zones 
apparently  representing  excessively  proliferated  cartilage  {J oachimsthal) . 
The  behavior  of  the  epiphysial  junctures  and  the  bone  nuclei  thus  vary 
according  to  the  intensity  of  the  process,  according  to  the  liveliness  of  the 
proliferation  of  the  abnormal  cartilage,  and  the  reparatory  processes. 
Rachitic  dwarfism  is  characterized  by  the  never-absent  signs  of  a  previous 
rachitis  and  by  the  normal  development  of  the  intelligence  and  of  genital  sphere. 

TV.  CHONDRODYSTROPHY 

{A  chondroplasia) 

Historical. — Chondrodystrophic  dwarfs  were  known  already  in  antiquity. 
Cestan  and  Meige,  who  have  concerned  themselves  with  the  historical  study 
of  this  disease,  refer  to  the  pictures  of  the  Egyptian  god  Ptah  and  the  goddess 
Bes,  in  which  typical  cases  of  chondrodystrophy  are  exhibited.  Also  the 
statue  of  Karakalla  and  several  pictures  by  Velasquez  show  typical  chondro- 
dystrophies. Formerly  chondrodystrophy  was  regarded  as  congenital  or  fetal 
rickets  {Sdmmering,  II.  Miiller,  Ldnger,  and  others).  Virchow  described  a 
chondrodystrophic  dwarf  that  he  regarded  as  a  case  of  endemic  cretinism. 
In  France,  Porak  denied  the  assumption  of  achondroplasia  as  fetal  rachitis  and 


CHOXDRODYSTROPHY  485 

set  forth  that  it  was  concerned  with  an  affection  of  the  epiphysial  cartilages 
that  sets  in  in  fetal  life.  Kanfmann  in  his  known  monograph  lines  himself 
against  Vircliow's  explanation.  Kaufmann  and  later  Diederle  have  done  away 
for  good  with  the  conception  of  a  thyrogenic  disturbance,  until  Kaufmann 
originated  the  name  chondrodystrophy,  by  which  the  condition  is  known  in 
Germany.  Kassowitz  calls  the  disease  "MikromeKe."  But  this  designa- 
tion is  not  precise,  as  there  are  dift"erent  kinds  of  micromelie  (shortness  of  the 
extremities)  that  have  nothing  to  do  with  chondrodystrophy  (osteogenesis 
imperfecta  [Vrolik],  phokomeKe,  etc.),  and  chondrodystrophy  constitutes 
only  one  of  these  types.  I  refer  the  reader  to  the  excellent  dissertation  of 
Siegert. 

Definition. — Chondrodystro pky  is  characterized  by  a  growth  disturbance 
of  the  cartilages  at  the  ossification  boundary  of  the  cartilages,  especially,  those 
of  the  long  hones  setting  in  the  earliest  fetal  life.  ^Microscopically  there  is 
found,  according  to  Kaifmann.  either  mucoid  softening  of  the  cartilages 
{malacic  form),  or  only  cessation  of  growth  (hypoplastic  form) ,  or  even  con- 
siderable, but  entirely  disorderly,  proliferation,  which  takes  place  in  all 
directions  instead  of  in  the  longitudinal  direction,  and  thus  leads  to  a  mod- 
erate sw^elling  out  of  the  epiphyses  {hyperplastic  form) .  In  older  indi\dduals, 
the  cartilaginous  zone  of  proliferation  is  bounded  at  the  periphery  by  strips 
of  connective  tissue  {Diederle) .  Thereby  the  periosteal  bone  formation  is  not 
inhibited,  and  may  even  be  excessive,  as  is  also  the  formation  of  bone  nuclei 
in  the  epiphyses,  which  may  even  show  acceleration.  The  disturbance  affects 
also  the  bones  of  the  skull  that  are  preformed  in  cartilage,  and  the  vertebral 
column,  while  the  growtli  of  the  bones  preformed  in  membrane  is  not  inhibited. 

Sjnnptomatology. — From  this  growth  disturbance  there  results  a  skeletal 
formation  characterized  by  the  follo-\^dng  points:  The  base  of  the  skull  is 
markedly  shortened  by  the  inhibition  of  growth  and  the  premature  synos- 
tosis of  the  OS  tribasilare  occipitalis  and  the  os  basilare  occipitalis,  as  first 
described  by  Virchow.  There  is  thus  brought  about  a  marked  retraction 
of  the  root  of  the  nose,  such  as  is  not  observed  in  any  other  growth  dis- 
turbance. There  are,  however,  rare  cases  of  chondrodystrophy  without 
this  retraction.  Eichholz  has  described  three  such  cases  belonging  to  one 
family.  Then  again  the  retraction  of  the  root  of  the  nose  ma}^  exist,  -^-ithout 
there  ha^dng  taken  place  a  coalescence  at  the  synchondrosis  (a  case  of  E. 
Langenhach) .  The  clivus  is  shortened — I  here  am  following  the  description 
of  Breus  and  Kolisko — the  foramen  magnum  is  very  small;  the  base  of  the 
skull  is  usually  supernormally  large;  there  occur  also  h3^drocephalic  skulls  in 
which  ossification  is  rather  retarded  so  that  the  f  ontanelles  persist  abnormally 
long.  The  form  of  the  sella  turcica  may  be  quite  abnormal  (confer  Ob- 
servation LXIII).  If  the  subject  fives  after  the  period  of  childhood,  the 
development  of  the  brain  and  the  intelligence  is  normal.  The  upper  jaws 
are  broad,  spread  far  apart,  and  the  upper  jaws  project  markedly.     Dentition 


486  VEGETATWE    DISTURBANCES 

is  entirely  normal.  The  vertebral  canal  is  narrowed,  usually  in  the  frontal 
diameter  on  account  of  premature  coalescence  of  the  nuclei  of  the  arches  and 
the  bodies,  but  sometimes  generally. 

There  exists  lordosis  of  the  lumbar  spine  and  kyphosis  of  the  thoracic 
spine.  The  thorax  is  narrowed  in  the  sagittal  diameter.  In  five  skeletons 
of  grown  chondrodystrophic  dwarfs,  Breus  and  Kolisho  found  frontal  stenosis^ 
of  the  vertebral  canal  in  every  case.  According  to  Diederle  the  narrowing 
may  also  be  conditioned  by  hyperplasia  of  the  cartilage.  This  was  true  in 
pronounced  manner  in  both  of  Lampe's  cases.  In  one  of  these  the  spinal 
medulla  was  markedly  compressed  on  this  account. 

In  chondrodystrophy  the  ribs  are  broad  and  coarse,  and  at  the  junctions 
of  the  ribs  the  cartilages  are  often  swollen-up  (pseudo-rosary),  in  such  a 
manner  that  the  bony  part  embraces  the  cartilaginous.  Sicgert  describes  a 
marked  swelling-out  at  the  part  of  the  rib  bordering  on  the  capitulum  costis, 
with  sharp-angled  bowing  and  fungus-like  swelUng  out  of  the  epiphysis;  the 
sternum  is  broad  and  thick,  body  and  xiphoid  process  are  synostosed;  the 
clavicles  are  short,  and  bent  in  the  form  of  an  S;  the  scapulae  very  small, 
their  borders  coarse,  the  pelvis  generally  narrowed,  its  inlet  kidney-shaped. 
The  promontory  [of  the  sacrum]  projects  markedly,  the  ilia  are  thickened, 
shovel-shaped  with  thickened  borders.  ^lost  characteristic  of  the  micro- 
melic  growth  disturbance  is  the  inhibition  in  growth  of  length  of  the  extremi- 
ties, which  is  the  proper  cause  of  the  dwarfism  of  the  individual.  Under 
normal  conditions  the  lower  length  begins  to  exceed  the  upper  length  already 
toward  the  end  of  the  first  year  of  life,  and  the  difference  becomes  more 
marked  as  the  years  pass.  In  the  disease  under  consideration  however  the 
growth  in  length  of  the  extremities  remain  so  far  behind  that  the  relation  of  tJie 
tipper  length  and  lower  length  may  reach  2:1.  As  the  periosteal  bone-forma- 
tion is  not  inhibited,  the  cortex  of  the  diaphyses  is  very  thick  and  very 
marked  places  for  the  insertions  of  the  muscles  develop;  the  muscles  themselves 
are  entirely  normal,  so  that  the  chondrodystrophic  dwarfs  are  very  strong  with 
regards  to  muscular  force  and  are  clever  acrobats.  According  to  Breus 
and  Kolisko  the  fibula  is  less  shortened  than  the  tibia,  so  that  it  projects 
markedly  below  the  lower  end  of  the  tibia,  thus  producing  a  varus  position 
of  the  foot;  the  feet  are  shortened,  also  the  upper  extremities  are  essentially 
shortened,  likewise  the  hand,  the  breadth  of  which  is  however  normal;  the 
shortened  fingers  stand  apart  from  one  another  (main  a  trident,  Radspeichen- 
form).  The  ossification  of  the  epiphyses  proceeds  very  irregularly.  The 
epiphyses  themselves  may,  as  Siegert  mentions,  sometimes  be  more  hyper- 
plastic, sometimes  more  hypoplastic,  in  the  latter  case  embracing  the  di- 
aphyses. The  closure  of  the  epiphysial  junctures  may  occur  prematurely, 
especially  those  of  the  metacarpal  bones  of  the  hands  and  feet;  at  other  places, 

^  In  German   edition  "sclerosis,"  according  to  the    original    article   of    Breus    and    Kotisok 
"stenosis." — Editor. 


CHONDRODYSTROPHY 


487 


however,  the  epiphyses  may  close  abnormally  late.  In  the  seventeen-year- 
old  case  I  shall  report  later,  the  distal  epiphysial  junctures  of  the  radius 
and  ulna,  and  the  proximal  of  the 
first  metacarpal  and  phalanges  are 
as  yet  wide  open,  so  that  exami- 
nation of  the  accompanying  X-ray 
picture  will  show  that  the  head  of 
the  metacarpal  bone  is  swollen 
out,  extremely  coarse,  and  that 
the  epiphyses  are  well  developed. 


\^' 


Fig.  86. — Chondrodystrophy  (Observation 
LXII). 


Fig.  87. — Chondrodystrophy  (Observation 
LXIII). 


and  in  part — for  example  those  of  the  radius  misplaced.     Hyperplastic  and 
hypoplastic  processes  may  often  be  seen  in  the  same  skeleton. 

There   have   also   been   described    cases   of   partial   chondrodystrophy. 


488 


VEGETATIVE    DISTURBANCES 


Dufour  describes  such  a  case,  in  which  the  upper  extremities  were  hardly 
shortened,  and  also  the  trident  form  of  the  hands  was  not  pronounced, 
while  the  lower  extremities  showed  marked  chondrodystrophic  alterations. 


Fig.  88. — X-ray  picture  of  the  hand  in  chondrodystrophy  (Observation  LXIII). 

Especially  noteworthy  is  the  case  of  unilateral  chondrodystrophy  described 
by  Siegeri  in  his  monograph. 

The  malacic  form  of  chondrodystrophy  is  not  capable  of  maintaining  its 


CHONDRODYSTROPHY  489 

life;  both  other  forms  may  attain  a  high  age.  The  aplastic  form  is  recogniz- 
able by  the  absence  of  the  vertebral  and  cranial  synostoses  described,  and 
further  by  a  characteristic  position  of  the  joints  by  which  the  extremities 


maintain  a  curved  appearance  {Breus  and  Kolisko).     The  dwarfs  are  for 
the  most  part  especially  small. 

For  the  characterization  of  the  chondrodystrophic  dwarf,  it  is  also  men- 
tioned that  they  all  show  a  great  family  likeness  [Porak) ;  that  the  gait  in  all 


490  VEGETATR'E    DISTURBANCES 

is  waddling,  that  the  intelligence  develops  normally,  and  that  finally  the  sexual 
glands  and  the  genitalia  develop  and  functionate  normally.  Indeed  in  many 
cases  the  genitaha  are  developed  remarkably  well. 

Here  are  set  forth  two  cases  observed  at  the  first  medical  clinic.  The 
notes  concerning  the  first  case,  four  years  old  (Observation  LXII).  have  un- 
fortunately been  mislaid.  I  can  only  show  the  characteristic  illustration, 
that  shows  the  characteristics  of  chondrodystrophic  dwarf  in  pronounced 
manner.  The  root  of  the  nose  is  markedly  retracted;  the  extremities  are 
enormously  shortened,  the  skin  has  become  too  wide  for  its  extremities, 
lying  in  thick  folds. 

Observation  LXII  I. — U.  W.,  seventeen  j^ears  old.  Father  of  the  patient  normally 
developed.  The  same  is  true  of  the  father's  parents  and  three  brothers  and  sisters  (except 
that  one  sister  has  a  syndactylism  of  three  fingers).  The  mother  of  the  patient  seems  to 
have  had  rickets  in  early  life,  but  is  of  normal  development.  Of  brothers  and  sisters  of 
the  patient  only  the  youngest,  a  girl  one  year  old,  is  living;  she  is  entirely  normal.  The 
eldest  child  died  at  the  age  of  fourteen  years  of  tuberculosis,  was  normally  developed. 
The  second  child  died  at  three-fourth  year,  the  third  at  one-fourth  year,  the  fourth  is  the 
patient.  The  fifth  and  sixth  died  at  one-fourth  and  one-half  years,  the  seventh  im- 
mediately after  birth. 

The  patient,  like  the  rest  of  the  children,  was,  according  to  statement,  normal  at  birth. 
At  six  months  of  age  he  seems  to  have  had  pain  in  passing  urine,  and  soon  after  the  father 
observed  that  the  child  remained  behind  in  growth,  and  only  the  head  was  much  too  large. 
The  increase  in  the  size  of  the  head  lasted  until  about  the  seventh  year.  He  learned  to 
speak  at  two  years,  the  intelligence  developed  entirely  normally.  At  about  one-half 
year  he  has  had  paresthesia  and  fatigue  in  the  legs.  He  began  to  walk  with  knees  pressed 
together  and  for  some  weeks  sitting  down  has  been  difficult  too. 

Height  125  cm.,  span  width  126  cm.,  acromion  to  points  of  finger  47  cm.;  upper  border 
of  trochanter  major  to  the  heel  53  cm.  Length  of  hands,  15  cm.,  breadth  10  cm.;  length 
of  feet  21  cm. 

The  cranial  skull  is  much  larger  than  the  facial  skull,  is  somewhat  quadrangular;  root 
of  nose  deepl}^  retracted.  On  looking  to  the  left  or  upward,  horizontal  or  vertical  nystag- 
mus respective!}'.  Chvostek's  phenomenon  present  on  both  sides.  Slight  dextroscoliosis  of 
the  thoracic  spine.  The  hands  are  short  and  broad,  the  fingers  alike  in  length,  typical 
mains  a  trident.  X-ray  shows  that  the  epiphysial  junctures  of  the  fingers  are  not  as  yet 
united.  The  sella  turcica  is  pressed  together  in  the  vertical  diameter,  broadened  in  the 
horizontal. 

The  musculature  is  normally  developed,  the  genitalia  hj-perplastic.  There  is  no  axil- 
lary hair,  nor  hair  on  the  linea  alba.  There  exists  a  moderatel}'  large  struma  of  rather  soft 
consistency. 

There  are  spasms  of  the  lower  extremities.  Legs  adducted  when  at  rest,  with  slight 
equinus  position.  Patellar  and  foot-clonus  present,  Babinski  positive.  Hypalgesia  and 
hyperesthesia  from  about  the  height  of  the  arch  of  the  ribs  downward,  becoming  less  from 
the  fossae  of  the  ilia  down;  very  slight  on  the  feet. 

Summary:  Typical  Chondrodystrophy. — At  first  we  thought  of  a  hydro- 
cephalus, descending  degeneration  of  the  pyramidal  tracts  and  spastic  paresis 
of  the  extremities.  Yet  there  were  no  other  points  for  our  adhering  to  the 
diagnosis  hydrocephalus.     It  is  possible  that  the  spastic  paresis  was  produced 


CHONDRODYSTROPHY 


491 


by  narrowing  of  the  vertebral  canal  by  the  chondrodystrophic  process.     I 
refer  to  the  case  of  Lampe  mentioned  above. 

Occurrence. — Chondrodystrophy  does  not  belong  to  exceedingly  rare 
affections.  According  to  Katolicky  about  70  cases  are  known  in  adults. 
Siegert  counts  53  females  and  50  male  cases.  Several  cases  of  familial  or 
hereditary  occurrence  of  chondrodystrophy  are  found  reported  in  the  litera- 
ture. Porak  mentioned  a  chondrodystrophic  female  dwarf  who  was  de- 
livered of  a  chondrodystrophic  child  through  Cesarean  section.  Porak  also 
cites  a  case  of  Charpentier,  a  twenty-three-year-old  chondrodystrophic 
female  dwarf,  whose  sister,  father  and  great-grandfather  had  been  chon- 
drodystrophic dwarfs.     Poncet  and  Leriche  observed  two  chondrodystrophic 


Fig.   90. — Chondrodystrophic  f amity  (Father— Observation  LXIV). 

sisters,  Decroly  saw  chondrodystrophy  in  grandfather,  father,  and  child. 
Also  Eichholtz  saw  famihal  occurrence  of  chondrodystrophy.  He  saw  two 
chondrodystrophic  sisters,  of  whom  one  was  a  childless  widow  forty-twiD 
years  old.  The  other,  about  forty  years  old,  had  an  eighteen-year-old 
chondrodystrophic  child.  She  was  dehvered  through  Cesarean  section. 
Also  the  father  of  both  women  seems  to  have  had  chondrodystrophy. 
Siegert  mentions  that  beyond  these  cases  he  could  find  no  others  of  m- 
heritance  of  the  disease  among  the  more  than  100  cases  reported  in  the 
hterature.  However,  there  are  later  observations.  Franchini  and  Zanasi 
observed  a  chondrodystrophic  man  and  wife.  The  woman  became  gravid 
and  was   delivered   through   Cesarean  section.     The   child,   which  indeed 


492 


VEGETATIVE   DISTURBANCES 


Fig.  91. 


Fig.  92. 


Figs.  91  and  92. — Chondrodystrophic  family  (Son — Observation  LXV  and  daughter— Observation  LXVl). 


CHOXDRODYSTROPHY  493 

the  authors  did  not  themselves  see.  was  80  cm.  tall  at  the  age  of  twelve  years, 
and  had  an  enlarged  head  and  shortened  extremities.  It  seems  thus  also  to 
have  been  a  chondrodystrophy,  as  the  authors  suppose  with  entire  correct- 
ness. Glaessner  showed  two  cases  of  chondrodystrophy  at  the  Wiener 
Gesellschaft  der  Arzte.  They  were  father  and  son.  fifty-six  and  twenty 
years  old,  loi  and  108  cm.  tall  respectively.  It  was  ehcited  that  for  four 
generations,  dwarfism  always  existed  in  the  male  members  of  the  family, 
while  the  women  were  entirely  normal.  A  fine  example  of  inheritance  of 
the  disease  was  also  observed  in  the  first  medical  clinic.  It  concerned  a 
father,  son,  and  daughter.  I  here  reproduce  the  photographs.  The  father 
was  forty-nine  years  old.  the  son  nineteen,  the  daughter  twelve  years  old. 
The  wife  of  the  father  was  of  normal  height.  (Observation  LXIV.  LXV, 
andLXVI). 

Etiology. — As  I  already  mentioned  at  the  beginning  chondrodystrophy 
was  first  regarded  as  fetal  rickets,  an  assumption  that  was  already  the  experi- 
ments of  Parrot  and  Porak  showed  unfounded.  Virchoii'  regarded  as  t^^pical 
for  endemic  cretinism  the  premature  synostosis  of  the  os  tribasilaris  that 
occurs  in  chondrodystrophy  and  on  this  supposition  turned  attention  to 
the  thyroid  gland  etiologically.  The  assumption  of  insufficiency  of  the 
thvroid  gland  is  recognized  as  incorrect,  as  the  result  of  the  works  of 
Kaiifmann  and.  later,  Diederle.  in  spite  of  which  Hertoghe.  Stotzner  and  Moro 
again  adopted  the  thyrogenic  origin  of  chondrodystrophy.  In  all  accurately 
investigated  cases  the  thyroid  gland  is  entirely  normal,  however  (Diederle, 
Breus  and  Kolisko,  Kassoivitz,  etc.).  The  supposition  of  Moro  that  in  his 
case  there  had  occurred  pre-\dously  a  dysplasia  of  the  thyroid  gland  is  not 
justified  bv  anvthing.  Also  in  the  case  reported  by  me,  there  was  not  a 
single  symptom  that  belonged  to  the  symptom-complex  of  h^-pothyrosis. 
Then  again  th3Toid  therapy  is  entirely  without  results,  even  in  young 
indi\dduals.  Recenth'  Sumita  has  set  forth  the  untenability  of  th}Toid- 
gland  therapy. 

Laiize  points  out  that  the  buft'oons  of  kings  were  chondrodystrophic  dwarfs 
who  have  been  described  as  talented,  loquacious,  quick  at  repartee,  "fond  of 
everything  that  glitters."  and  sometimes  also  as  maniacal.  Lauze  regards 
this  mental  condition  as  the  result  of  h}-persecretion  of  the  interstitial  glands. 
Eiiziere  and  Delmas  describe  a  case  of  chondrodystrophy  ^^-ith  psychical 
characteristics  such  as  Lauze  has  described;  they  regard  these  however  as  an 
expression  of  degeneration  and  do  not  beheve  that  such  psychical  earmarks 
stand  in  causal  associationship  with  chondrodystrophy.  In  the  cases  of 
chondrodystrophy^  observed  by  me  I  could  not  observe  any  of  the  mental 
characteristics  described  by  Lauze.  The  hypothesis  of  Lauze  should  hardly 
gain  adherents. 

Differential  Diagnosis. — Nowadays  we  ought  not  to  waste  words  con- 
sidering the  differential  diagnosis  from  cretinism. 


494 


VEGETATIVE    DISTURBANCES 


Another  form  of  micromelic  growth  disturbance,  osteoporosis  congenita 
{Kundrat),  is  characterized  by  a  disturbance  of  the  epiphysial  as  well  as  peri- 
osteal bone  formation.  Clinically,  it  has  up  to  the  present  been  without 
significance  as  the  infants  have  never  been  capable  of  maintaining  life;  ex- 
cept that  Hagenhach  described  a  dwarf  with  tumor  of  the  hypophysis, 
whose  bone  alterations  Hagenhach  regarded  as  osteoporosis.  Up  to  the  pres- 
ent there  are  no  tenable  relationships  between  this  disease  and  the  ductless 
glandular  system. 

V.  MONGOLISM 

{Mongoloid  Idiocy) 

Mongolism  was  first  recognized  as  a  disease  sui  generis  by  Langdon-Down. 
I  shall  here  limit  myself  to  a  short  dehneation,  paying  especial  attention  to 


Fig.  93. — Six  and  one-half-year  old  girl  (Mongolism)  witli  three-year-old  healthy  sister. 

the  differential  diagnosis  from  infantile  myxedema,  in  the  course  of  which 

I  follow  the  excellent  descriptions  of  Bourneville,  Kassowitz,  Scholtz,  and  Siegert. 

Symptomatology. — The  Mongoloid  children  show  a  great  family  likeness. 

The  term  Mongolism  is  used  because  the  physiognomy  of  these  children  shows 


MONGOLISM 


495 


great  similaritv  to  that  of  the  ^MongoHan  races.  While  in  infantile  mvx- 
edema  the  skull  is  mostly  large  and  pronouncedly  brachycephahc.  in  ]Mongol- 
ism  it  is  small  and  round,  the  palpebral  fissures  are  small  and  lack  myxedema- 
tous swelling,  they  are  placed  oblique,  are  sht-like  and  show  epicanthus; 
the  nose  is  small  and  sits  Kke  a  button  on  the  broadened  and  somewhat 
sunken  nose-root  (Kassowitz) ,  while  in  infantile  myxedema  the  root  of  the  nose 
is  strongly  retracted,  so  that  the  nasal  cavities  become  apparent.  Mongo- 
loids often  show  a  conjunctivitis.     The  zygomatic  arches  protrude  somewhat. 


Fig.  94. — Same  case  after  thyroid  treatment. 


the  forehead  is  low  and  flat,  the  mouth  is  small  but  becomes  broad- 
ened when  the  patient  laughs,  the  tongue  is  not  enlarged,  or  not  essentially 
so,  is  fissured,  is  always  somewhat  between  the  separated  rows  of  teeth,  the 
lower  jaw  as  a  rule  projects  beyond  the  upper  jaw.  The  palatal  arches  are 
high,  the  cephalic  hairs  are  soft  and  silk-like,  while  in  myxedema  the}'  are 
rough  and  dry  and  are  here  and  there  absent.  The  ears  are  small  and 
stand  back,  the  lobules  have  developed  in  the  form  of  a  triangle  (oreille 
mongolienne) ,  the  facial  expression  is  morose  and  unintelligent.j^in  ^Mongol- 
ism  it  is  vacant  and  expressionless  only  in  the  first  years  of  life.     Later  it 


496 


VEGETATR'E    DISTURBANCES 


is  gay.  comical,  imbecile.  I  refer  to  the  accompanying  illustration.  The 
cheeks  lack  the  thickness  of  myxedema  and  usually  show  a  macular  red- 
ness. WTiile  in  infantile  myxedema  or  thyroaplasia  the  condition  becomes 
recognizable  only  some  time  after  birth,  ^Mongolism  may  be  recognized 
immediately  "c'est  un  petit  chinois.""  The  fontanelles  and  sutures  are  open 
abnormally  long,  dentition  is  somewhat  delayed  and  somewhat  irregular. 
The  teeth  are  defective,  and  the  set  of  teeth  mostly  shows  numerous  ab- 
normalities. (Degenerationsgebiss-Fo^/);  growth  in  height  is  usually 
somewhat  stunted,  but  there  exists  a  difference  from  infantile  myxedema 


in  that  all  these  manifestations  are 
bone  nuclei  usually  appear  at  the 
many  a  case  only  isolated  bone  n 
observed  premature  ossification  of  t 
occurs  a  stunting  of  growth,  and  e 
been  observed  by  Bourneville.  The 
lipomata  of  infantile  myxedema  an 
obesity.  The  neck  is  regular,  nol 
The  thyroid  is  present.  Very  comr 
tion  exists,  and  umbilical  hernias  a 
hernias  forty-four  times  among  fift 
the  linea  alba  below  the  umbilicus 
(Observation  LXVII)  for  which  I  t 
Mongolian  expression  of  the  face. 

The  skeleton  is  proportioned,  sll 
late,  the  hands  are  rather  small,  aj 
finger  is  often  shortened,  the  end  p 
very  short  (main  mongolienne). 
ordinarily  low,  especially  the  joint 
joints.  The  musculature  is  ofte 
formation  occur,  such  as  congenii 
strabismus  or  nystagmus.  The  i 
fantile  myxedema,  in  that  they  reL....x.  ^.^j  ^  .....^  ^^.....^  xn  ^development. 
In  males,  the  penis  and  scrotum  are  often  strikingly  small,  as  Kassowitz  found 
nineteen  times  in  thirty-nine  cases,  and  Siegert  in  half  the  cases.  Also  there 
may  be  delay  in  descent  of  the  testicles.  Later  the  genital  functions  are  for 
the  most  part  normal,  although  libido  may  be  very  slight.  The  Mongoloids 
are  usually  short-lived,  and  very  sensitive  to  tuberculosis.  The  mental 
development  is  most  only  delayed,  or  there  may  be  slight  imbecility— and 
but  rarely  pronounced  idiocy.  The  children  are  rather  lively,  but  their 
attention  is  fixed  with  difficulty;  they  have  considerable  imitability  and  pose 
readily. 

Hence  there  are  very  few  features  of  infantile  myxedema  mixed  in  with 
Mongolism.     These  are  eventually  a  slight  degree  of  dwarfism,  the  delay  of 


d.  and  the 
later.  In 
'iegert  even 
there  often 
/arfism  has 
he  pseudo- 
sts  marked 
myxedema, 
id,  obstipa- 
d  umbilical 
a  hernia  in 
[lustrations, 
3),  show  the 

t  and  stand 
of  the  little 
imb  is  often 
.  are  extra- 
Iso  the  hip- 
nomalies  of 
rarely  slight 
those  of  in- 


ADDENDUM  497 

the  dentition  and  closure  of  the  fontanelles,  the  distention  of  the  abdomen, 
the  umbilical  hernias,  the  constipation,  the  remaining  behind  in  mental 
development,  the  anemia.  There  are,  however,  cases  of  Mongolism  in  which 
myxedematous  symptoms  are  more  prominent;  Vogt,  Neurath,  and  others 
have  described  such  cases. 

Pathogenesis  and  Treatment. — From  what  has  been  said,  we  should 
expect  that  thyroid-gland  treatment  would  have  only  a  slight  influence. 
Sometimes  not  even  acceleration  of  the  dentition  and  closure  of  the  fonta- 
nelles follow.  Only  the  umbilical  hernia  and  constipation  are  improved 
rapidly.  Kassowitz  says  that  in  young  children  treatment  with  thyroid 
gland  will  only  anticipate  the  improvement  that  later  occurs  spontaneously. 
In  the  case  shown  above,  the  results  of  its  use  may  be  regarded  as  extraor- 
dinarily good. 

Although  according  to  what  has  been  said  there  tends  to  be  present  in 
cases  of  Mongolism  a  slight  temporary  component  of  athyrosis,  which  may  be 
more  strongly  pronounced  in  certain  rare  cases,  yet  there  is  not  doubt  that 
the  clinical  picture  of  this  disease  cannot  be  attributed  to  any  disease  of 
the  thyroid.  This  is  confirmed  by  the  fact  that  in  the  few  autopsies  thus 
far  recorded  the  thyroid  for  the  most  part  was  found  to  be  normal  {Neumann, 
Comhy,  Bourneville) .  Only  Phillippe  and  Oherthur  found  in  four  cases 
inflammatory  sclerosis  and  Lange  slight  inflammatory  changes.  Bourneville 
in  five  cases,  and  Sieger t  in  one  case  saw  a  persistent  thymus.  The  findings 
in  Mongolism  do  not  present  anything  characteristic,  and  resemble  those  of 
idiocy  (Scholz).  Kassowitz  considers  the  simultaneous  aft'ection  of  many 
ductless  glands;  which  assumption  lacks  all  objective  evidence.  Most 
worthy  of  remark  in  an  etiological  direction  seems  to  me  the  oft  repeated 
observation  that  Mongoloids  are  the  last  born  in  a  family  numerous  in 
children,  or  that  the  mother  was  very  old  or  her  strength  had  been  reduced 
through  illness.  ShuUleworth  therefore  terms  the  Mongoloids  the  "products 
of  exhaustion." 

In  the  diferential  diagfiosis  from  infantile  myxedema,  the  X-ray  examina- 
tion, in  addition  to  the  Mongoloid  expression  of  the  face,  is  of  importance. 

Addendum 

It  is  true  that  no  term  in  medicine  has  been  more  abused  than  that 
of  "infantilism,"  and  that  any  special  work  done  on  the  individuals  aft'ected 
with  infantilism  must  be  accepted  with  caution  if  the  type  of  infantilism 
and  exact  description  of  the  individual  be  not  clearly  stated.  The  author's 
attempt  to  delimit  the  affection  is  indeed  very  laudable;  but  it  is  true  that  the 
determination  of  the  fine  shades  of  distinction  is  often  very  difficult.  Thus 
certain  of  the  cases  of  pituitary  tumor  without  apparent  abnormal  distribu- 
tion of  fat  have  been  classed  under  the  general  term  "infantilism."  It  is 
32 


498  VEGETATIVE    DISTURBANCES 

not  at  all  certain  that  these  cases  would  be  included  under  any  of  the  types 
mentioned  by  the  author,  although  some  do  possess  features  that  resemble 
closely  the  infantile  types.  Among  these  may  be  mentioned  the  type  of 
"fat  boy"  described  by  Gushing,  which  Gushing  regards  as  on  the  whole  a 
hypopituitarism. 

The  various  types  of  dwarfism  present  fairly  well-defined  characteristics. 

McKee,  who  has  had  an  extensive  experience  with  Mongoloids,  claims 
to  have  attained  very  good  results  from  the  use  of  thyroid-gland  extracts. 

References 

Cushing,  (H.).  Concerning  the  symptomatic  differentiation  between  disorders  of  the 
two  lobes  of  the  pituitary  body:  with  notes  on  a  syndrome  accredited  to  hyperplasia  of  the 
anterior  and  secretory  stasis  or  insufficiency  of  the  posterior  lobe.  Am.  J.  M.  Sc,  March, 
1913,  PP-  313-328. 

McKee  and  Wells.  Practical  Pediatrics.  Vol.  II,  p.  625,  Philadelphia,  P.  Blakiston's 
Son  &  Co. 


CHAPTER  XIII 

THE  DISEASES  OF  THE  INSULAR  APPARATUS  OF  THE  PANCREAS 
AND  THEIR  RELATION  TO  DIABETES  MELLITUS 

A  description  of  the  pathology  of  the  inner  secretion  of  the  pancreas 
offers  beforehand  many  greater  difficulties  than  that  of  other  ductless  glands, 
especially  if  the  clinical  manifestations  are  chiefly  considered.  The  pancreas 
is  not,  like  the  other  ductless  glands,  exclusively  a  gland  with  internal  se- 
cretion. It  belongs  to  the  most  important  glands  of  external  secretion;  and 
anatomically  shows  chiefly  the  structure  of  one  of  these.  Actually  the 
physiology  and  pathology  of  the  external  secretion  of  the  pancreas  was  for  a 
long  time  the  subject  of  investigation,  before  chnical  observations,  and  then 
the  experiments  on  the  total  extirpation  of  the  pancreas,  led  us  to  think  of 
the  possibihty  that  the  pancreas  might  have  an  internal  as  weh  as  an  external 
secretion. 

Historical  Development. — Already  Bouchardat  had  observed  sclerotic 
alterations  of  the  pancreas  in  some  cases  of  diabetes  mellitus,  and  on  the 
ground  of  these  observations  had  expressed  the  opinion  that  the  cause  of 
human  diabetes  depended  on  a  disease  of  the  pancreas.  A  secure  experi- 
mental foundation  for  this  view  was  first  created  by  the  celebrated  ex- 
periments of  -0.  Mering  and  Minkowski.  These  investigations  showed  that 
total  extirpation  of  the  pancreas  in  dogs,  in  addition  to  the  disturbances 
of  absorption  due  to  the  absence  of  the  pancreatic  juice,  leads  regularly  to 
an  excretion  of  sugar,  indeed  even  to  a  severe,  fatally  ending,  diabetes. 

First  through  this  discovery  was  the  interest  of  pathological  anatomists 
turned  in  general  toward  the  pancreas.  In  the  course  of  the  next  decade  there 
followed  numerous  statments  as  to  various  alterations  of  the  pancreas  in 
diabetes  mellitus,  sclerotic  changes,  inflammatory  processes,  etc. ;  yet  in  spite 
of  the  weight  of  the  experimental  finding,  we  could  not  overlook  the  fact  that 
in  many  cases  of  severe  diabetes  mellitus  the  pancreas  showed  no  demon- 
strable pathologico-anatomical  alteration  and  that,  on  the  other  hand,  in 
many  cases  of  high-grade  destruction  of  the  pancreatic  tissue,  diabetes  was 
entirely  absent.  The  question  assumed  another  aspect  when  attempts  were 
made  to  bring  the  islands  formerly  described  by  Langerhans  into  relation 
with  the  inner  secretion  of  the  pancreas.  While  the  glandular  acini  furnish 
the  external  secretion,  the  islands  of  Langerhans  might  constitute  an  em- 
bryologically  independent  tissue  element  distributed  throughout  the  entire 
pancreas,  which  might  give  off  directly  into  the  blood  path  a  hormone  im- 
portant for  carbohydrate  metabolism.     Especially  important  for  this  view 

499 


500  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

was  the  observation  of  Ssoholew  and  of  Schuize,  that  after  ligation  of  the 
excretory  duct  of  the  pancreas,  the  acinous  tissue  gradually  undergoes  atro- 
phy while  the  islands  remain  intact.  Also  the  observations  of  the  patho- 
logical anatomists  show  that  the  islands  are  much  more  refractory  toward 
the  action  of  various  noxious  agents  than  is  the  acinous  tissue.  This  furnishes 
the  explanation  of  the  numerous  cases  of  severe  disease  of  the  pancreas  without 
glycosuria;  on  the  other  hand  statements  that  in  diabetes  mellitus  chiefly  the 
islands  diseased  were  constantly  increasing,  a  direction  that  was  first  inau- 
gurated by  Opie  and  quite  particularly  upheld  by  Weichselhaum.  Up  to  the 
present  the  insular  theory  has  not,  however,  won  general  recognition,  as  it  is 
found  on  the  pathological  anatomical  side  that  there  are  constantly  occurring 
cases  in  which  in  spite  of  an  existing  diabetes  the  insular  tissue  remains  intact 
and  even  in  certain  cases,  is  especially  well  developed.  This  finding  has  led 
many  authors  to  the  view  that  both  tissue  elements  of  the  pancreas,  acinous 
and  insular  apparatus,  produce  the  hormone.  In  recent  years  the  problem 
of  the  internal  secretion  of  the  pancreas  has  experienced  further  complication; 
the  view  has  been  expressed  that  the  significant  influence  that  the  pancreas 
exercises  over  digestion  in  the  intestine  depends  not  alone  on  the  enzymatic 
properties  of  the  intestinal  juice  but  in  part  on  the  internal-secretory  activity 
of  the  pancreas  {Lombroso) .  Both  tissue  elements  of  the  pancreas,  according 
to  this,  are  involved  in  both  the  external  as  well  as  the  internal-secretory 
activities.     This  teaching  has  obviously  caused  much  confusion. 

Another  aspect  of  the  problem  is  the  question  how  the  pancreas  takes 
part  in  the  carbohydrate  metabolism.  Claude  Bernard  assumed  that  in  dia- 
betes there  was  increased  sugar  production.  Afinowski  first  expressed  the 
opinion  that  on  the  absence  of  the  pancreatic  hormone  the  consumption  of 
the  sugar  molecule  in  the  body  suffers  harm.  Naunyn  inclines  more  to  the 
view  of  a  disturbance  in  glycogenesis  (dyszoamylie).  LiitJije  first  furnished 
the  certain  demonstration  that  in  addition  to  the  carbohydrates  also  the 
protein  is  to  be  considered  as  a  sugar  builder.  The  increase  in  the  sugar 
production  has  been  more  discussed  again  since  the  investigation  of  O.  Ldwi; 
Eppinger,  Falta,  and  Rudinger  assume  in  experimental  pancreatic  diabetes 
both  reduction  in  the  sugar  consumption  (removal  of  the  specific  internal 
secretion)  as  well  as  increase  in  the  mobilization  of  sugar  (consecutive 
increase  of  function  of  the  chromafiin  tissue),  a  view  that  /  promulgated  for 
human  diabetes.  On  the  ground  of  the  investigations  of  Forges  and  Salomon, 
V.  Noorden  brought  the  increased  sugar  production  again  into  the  foreground, 
while  lately  Starling  and  Knouthon  have  advocated  the  exclusive  disturbance 
of  sugar  combustion. 

As  to  what  finally  is  the  significance  of  the  pancreas  for  the  pathogenesis 
of  human  diabetes  views  diverge  greatly.  The  discovery  of  sugar  puncture 
by  Claude  Bernard  led  to  the  viewing  of  each  case  of  diabetes  as  neurogenic. 
After  the  discovery  of  experimental  pancreatic  diabetes,  attention  was  drawn 


ANATOMY  AND  EMBRYOLOGY  50I 

on  the  contrary  to  the  pancreas.  Of  course  between  the  experimental  pan- 
creatic diabetes  and  the  genuine  human  diabetes  there  exist  considerable  dif- 
ferences. The  intensity  of  the  glycosuria  is  much  higher  in  the  latter. 
In  association  with  Grote  and  Staehelin,  I  have  pointed  to  the  enormous  in- 
crease in  the  decomposition  of  protein  and  the  respiratory  exchange  of  gases 
in  experimental  pancreatic  diabetes.  In  genuine  human  diabetes  on  the 
other  hand  the  demand  for  protein  as  well  as  the  demand  for  calories  is  not 
increased.  The  supposition  of  Benedict  and  Joslin  that  the  heat  production 
in  human  diabetes  is  increased  I  cannot  subscribe  to,  the  reason  for  which  I 
shall  detail  later.  In  consideration  of  these  essential  differences  /  have  taken 
position  as  regards  the  pathogenesis  of  human  diabetes  in  a  direction  contrary 
to  the  pancreatocentric;  as  also  v.  Noorden,  on  the  ground  of  his  clinical  ex- 
perience and  the  investigations  carried  out  in  his  cKnic,  has  upheld  the  view 
that  in  addition  to  the  pancreas,  a  high  value  must  be  ascribed  to  the  chromaf- 
fin tissue  or  the  nervous  system. 

In  addition  to  the  pancreas  and  the  chromaffin  tissue,  the  thyroid  gland 
is  certainly  of  importance  in  the  genesis  of  many  diabetic  glycosurias. 

The  manner  of  procedure  in  the  following  dissertations  must,  in  order  to 
render  possible  a  condensed  exposition  of  the  manifold  and  complex  questions 
deviate  in  some  points  the  scheme  followed  thus  far.  After  some  introduc- 
tory remarks  as  to  the  anatomy  and  embryology  of  the  pancreas  the  results 
of  the  experimental  investigation  will  be  given  more  space  than  has  been  the 
case  in  the  other  chapters.  Especially  will  I  treat  in  detail  the  metabolic 
disturbances  that  occur  in  animals  after  total  extirpation  of  the  pancreas. 
Also  experimental  nervous  diabetes,  so  far  as  it  has  not  already  been  con- 
sidered in  the  chapter  on  the  suprarenals,  will  be  dwelt  on.  In  the  chnical 
part,  I  shall  first  describe  the  gross  anatomical  disturbances  of  the  pancreas 
simultaneously  with  the  accompanying  alterations  of  metabolism.  Then  wiU 
follow  a  short  exposition  of  the  clinical  manifestations  of  genuine  diabetes  as 
far  as  this  is  necessary  in  order  to  emphasize  the  points  of  dift'erence  from  the 
changes  in  metabolism  in  experimental  pancreatic  diabetes.  The  patho- 
logical anatomy  of  genuine  diabetes  mellitus  will  be  treated  more  in  detail, 
however,  including  a  consideration  of  the  alterations  of  the  pancreas,  as  weU 
as  those  of  the  central  nervous  system.  Only  then  will  I  enter  into  the 
question  as  to  what  role  the  inner  secretion  of  the  pancreas,  or  the  patho- 
logico-anatomical  alterations  of  the  insular  apparatus,  play  in  the  pathogene- 
sis of  diabetes  mellitus. 

Anatomy  and  Embryology.- — The  pancreas  is  a  long-drawn-out  cylindrical 
organ,  situated  behind  the  stomach  just  in  front  of  the  pars  lumbahs  of  the 
diaphragm.  We  distinguish  from  right  to  left,  the  broad  head  lodged  in  the 
loop  of  the  duodenum,  the  neck,  the  body,  and  the  tail.  The  head  is  inti- 
mately adherent  to  the  loop  of  the  duodenum,  while  the  left  end  (processus 
uncinatus)  is  more  movable.  On  its  anterior  surface,  the  pancreas  is  covered 
with  peritoneum.     The  length  of  the  organ  is  about  19-22  cm.,  the  weight. 


502  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

according  to  Vierordt  varies  between  85  gm.  and  105  gm.,  according  to  Orth 
between  90  gm.  and  120  gm.  The  pancreas  is  extraordinarily  well  vas- 
cularized. It  receives  a  large  branch  (arteria  pancreatico-duodenalis  supe- 
rior) from  the  ramus  gastroduodenalis  of  the  hepatic  artery,  further  several 
branches  from  the  splenic  artery,  and  one  branch  (arteria  pancreatico-duo- 
denalis inferior)  from  the  superior  mesenteric  artery.  The  pancreas  is  sup- 
plied by  an  abundant  nerve  plexus  of  branches  from  the  vagus  and  from  the 
sympathetic  fibers  that  emanate  from  the  sympathetic  trunks  or  from  the 
great  sympathetic  ganglia. 

The  glandular  acini  of  the  pancreas  form  large  lobes  bound  together  by 
loose  connective  tissue  that  are  in  turn  made  up  of  smaller  lobules.  The 
excretory  ducts  of  the  acini  unite  in  the  pancreatic  duct  or  duct  of  Wirsung, 
which  empties  in  common  with  the  ductus  choledochus  into  the  papilla  of 
Vater  in  the  duodenum.  A  large  excretory  ductus  pancreaticus  accessorius, 
emanating  from  the  head,  unites  with  the  duct  of  Wirsung.  From  the  acces- 
sory duct  there  usually  branches  a  duct  uniting  with  the  duodenum  (ductus 
Santorini).  Opie  found  this  duct  obliterated  or  markedly  narrowed  in 
numerous  cases.  Only  in  such  cases  w^as  the  secretion  of  the  pancreas  fully 
cut  off  from  the  intestine  by  closure  of  the  principal  duct.  The  closure  of 
the  accessory  duct  may  lead  to  isolated  sclerosis  of  the  head  of  the  pancreas. 
Further,  we  should  consider  that  not  infrequently  accessory  lobules  of  the 
pancreas  are  found  in  the  duodenum. 

In  the  lobules  of  the  glandular  parenchyma  are  found  imbedded  betw^een 
the  individual  acini  cell  groups  that  consist  in  polygonal  cells  with  large  round 
nuclei.  These  cells  stain  less  distinctly  than  the  cells  of  the  acini.  The  pro- 
toplasm is  lighter,  it  does  not  show  the  distinct  zymogen-granules  as  does  the 
glandular  tissue.  These  cell  groups,  which  occur  in  very  different  number 
and  size,  are  named  after  their  discoverer,  the  island  of  Langerhans.  They 
are  found  in  all  kinds  of  animals  (Diamare) ,  and  in  some  they  are  very  large 
and  even  visible  macroscopically.  They  show  an  especial  abundance  of 
blood-vessels.  The  capillaries  form  a  dense  network  interlarding  the  cell 
groups  similar  to  what  we  see  in  the  renal  glomerules  (Kuhnc  and  Lea).  The 
cell  accumulations  have  no  connection  with  the  excretory  ducts  of  the  gland. 
They  are  never  filled  after  the  injection  of  the  excretory  ducts  {v.  Ehner). 
Many  histologists  state  that  the  islands  of  Langerhans  are  surrounded  by  a 
capsule  {Renaut,  Opie,  Flint,  and  others).  Others  combat  the  existence  of  a 
capsule  (Diamore,  Hansemann,  and  others).  At  any  rate  it  should  be  men- 
tioned that  in  many  species  of  animals  (for  example  in  the  cartilaginous  fishes) 
the  capsules  are  found  constantly  {Rennie). 

Very  different  views  have  been  expressed  as  to  the  nature  of  these  pic- 
tures. Langerhans  regarded  them  as  nervous  structures,  later  authors  as 
lymph  follicles.  Finally  the  view  was  promulgated  that  they  constitute  a 
gland  with  internal  secretion  distributed  throughout  the  entire  pancreas, 
that  gives  off  an  internal  secretion  to  the  interlarding  capillary  network. 


DIABETES    AFTER    EXTIRPATION    OF    THE    PAXCREAS  503 

According  to  the  views  of  these  authors  the  islands  of  Langerhans  are  com- 
pletely independent.  On  the  other  hand  authors  state  that  the  insular  tissue 
may  shade  off  into  the  glandular  tissue  and  vice  versa.  Laguesse  first  de- 
scribed intermediary  forms  between  the  gland  cells  and  the  island  cells,  and 
assumed  that  on  certain  functional  demands  there  was  a  transition  from  the 
one  kind  of  tissue  into  the  other  (balancement) .  Karakaschef  is  of  the  opin- 
ion that  the  islands  constitute  only  a  sort  of  reserve  material,  and  that  under 
certain  conditions,  for  examples,  in  the  giving-out  of  gland  tissue,  there  enters 
into  play  a  regeneration  of  the  parenchyma  from  the  islands.  On  the  other 
hand.  Gutmann  would  see  a  changing  of  the  parenchyma  into  insular  tissue. 
Also  Swale  Vincent  and  Thompson  suppose  transitions  between  the  gland 
cells  and  the  island  cells.  The  recent  embryological  studies  and  investiga- 
tions as  to  the  regeneration  processes  in  the  pancreas  do  not  seem  to  confirm 
the  opinion  of  these  authors. 

The  pancreas  is  of  entodermal  origin.  There  are  present  three  rudiments, 
a  dorsal,  made  up  of  the  epitheKum  of  the  primitive  duodenum,  and  two  ven- 
tral proceeding  from  the  groove-shaped  rudiment  of  the  ductus  choledochus. 
Laguesse  first  showed  that  the  islands  as  well  as  the  glandular  parenchyma  is 
of  epithelial  origin,  and  also  showed  that  the  islands  separate  out  from  the 
primitive  cell  columns  at  the  same  time  as  the  glandular  tissue.  The  newer 
investigations  on  human  fetuses  (Pearce,  Weichselhaiim  and  Kyrle.  Mironescii) 
leave  room  for  no  doubt  that  the  island  tissue  already  in  earliest  fetal  life 
develops  from  the  epithelial  cell  columns  just  as  do  the  acini. 

The  youngest  fetus  in  which  the  islands  of  Langerhans  were  observed  was 
54  mm.  long  iPearce).  Weichselbaum  and  Kyrle  did  not  find  them  present 
as  yet  in  a  fetus  50  mm.  long.  The  islands  are  first  found  in  the  distal  part 
of  the  pancreas.  Also  in  adults  they  are  more  frequent  in  the  tail  of  the  pan- 
creas iOpie).  r.  Hansemann  assumed  that  the  islands  were  of  mesenchy- 
mal origin,  but  Weicliselhaum  and  Kyrlc  iound  them  also  later  still  in  asso- 
ciation "^dth  the  excretor\-  duct  of  the  pancreas,  and  hence  regarded  them  as 
entodermal.  ^Moreover,  also  the  observations  as  to  the  regenerative  processes 
in  the  pancreas  after  abundant  destruction  of  glandular  tissue  show  that  the 
islands  always  develop  from  the  excretory  duct  {Ssoholew,  Kyrle) ;  especially 
beautifully  do  the  investigations  of  Kyrle  show  that  on  implantation  of  pieces 
of  pancreas  into  the  spleen,  in  the  regeneratiA-e  processes  that  soon  make  their 
appearance,  the  island  and  acinous  tissue  develop  independently  out  of  the 
epithelium  of  the  excretory  duct. 

I.  EXPERIMENTAL  PART 

A.  Diabetes  after  Extirpation  of  the  Pancreas 

"We  shall  first  describe  carbohydrate  metabolism  after  extirpation  of  the  pan- 
creas.    The  complete  extirpation  of  the  pancreas  causes  in  all  kinds  of  ani- 


504  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

mals  disturbances  in  the  metabolism  of  sugar.  It  is  true  that  in  certain 
species  of  birds  this  does  not  go  as  far  as  glycosuria,  but  there  results  a  hyper- 
glycemia. The  significance  of  the  pancreas  for  the  metabolism  of  sugars  is 
therefore  universal.  The  extirpation  of  the  organ  in  dogs  has  been  studied 
the  most  exactly;  I  shall  therefore  make  especially  the  observations  in  the 
experiments  on  dogs  the  foundation  of  the  following  dissertation.  The 
complete  removal  of  the  pancreas  in  dogs  always  causes  a  diabetes.  The 
negative  results  that  were  obtained  by  certain  investigators,  especially  those 
who  preceded  Mering  and  Minkowski,  and  referred  to  the  facts  that  total  ex- 
tirpation of  the  pancreas  is  very  difficult,  and  that  sometimes  slight  remnants 
suffice  to  prevent  the  outbreak  of  the  disease.  L'uthje  has  contributed  still 
later  reports  in  which  in  spite  of  complete  extirpation,  the  glycosuria  remained 
absent.  There  occurred,  however,  as  Li'itlije  himself  stated,  hyperglycemia 
after  the  operation,  and  later  histological  examinations  of  the  duodenum 
showed  that  remnants  of  pancreatic  tissue  were  present.  In  more  than  forty 
experiments  that  we  ourselves  have  instituted  in  the  course  of  the  last  year, 
like  Minkowski  we  never  missed  the  occurrence  of  a  severe  diabetes.  When 
about  a  third  of  the  organ  is  left  behind,  diabetes  usually  remains  absent,  but 
can,  however,  develop  later  if  the  piece  left  behind  undergoes  inflammatory 
processes.  If  a  still  smaller  piece  of  the  pancreas  is  left  behind,  there  occurs 
a  light  diabetes,  that  is,  excretion  of  sugar  occurs  only  when  the  carbohydrate 
metabolism  is  overstrained  by  the  administration  of  a  diet  rich  in  amylaceous 
material  {Sandnieyer^s  diabetes). 

The  sugar  that  is  excreted  in  the  urine  after  the  total  extirpation  of  the 
pancreas  is  grape-sugar.  The  sugar  elimination  usually  starts  only  a  few 
hours  after  the  operation  and  in  about  forty-eight  hours  the  diabetes  is  at 
its  height.  Before  the  death  of  the  animal  the  excretion  of  sugar  usually 
gradually  sinks.  The  duration  of  life  after  the  operation  is  at  the  most 
fourteen  days.  Exact  information  as  to  the  intensity  of  the  excretion  of  sugar 
is  furnished  by  the  excellent  work  of  Minkowski.  This  author  showed  that 
administration  of  sugar  raises  the  existing  glycosuria  by  the  amount  ad- 
ministered, and  further  that  at  the  height  of  the  disturbance  in  metabolism 
the  amount  of  excreted  sugar  bears  a  definite  relation  to  the  amount  of  ex- 
creted nitrogen.  This  quotient,  D:N,  remains  2.8  to  3  [:i],  just  as  well 
when  the  dog  is  fasting  as  when  it  is  fed  with  meat  or  other  albuminous  body. 
Minkowski  hence  drew  the  conclusion  that  in  this  quotient  is  expressed  the 
extent  to  which  the  animal  organism  is  enabled  to  form  sugar  out  of  protein. 
The  animals  become  poor  in  glycogen  extraordinarily  rapidly.  After  forty- 
eight  hours  the  liver  is  almost  free  of  glycogen  and  later  becomes  highly 
fatty.  The  glycogen  is  retained  in  the  muscles  for  a  long  time,  however. 
Even  the  leucocytes  are  strikingly  rich  in  glycogen.  Administration  of 
grape-sugar  cannot  halt  the  disappearance  of  glycogen.  The  power  of  form- 
ing glycogen  does  not  however  disappear  entirely,  for  on  the  administration 


DLAJBETES    AFTER    EXTIRPATION    OF    THE    PANCREAS 


0^3 


of  levulose  a  part  of  the  same  may  be  deposited  as  glycogen,  in  which  case,  as 
Eppinger  and  /  observed,  also  the  fattening  of  the  liver  is  halted.  A  part 
of  the  levulose  is  excreted  as  levulose,  another  part  as  glucose.  The  ques- 
tion as  to  whether  the  increase  in  elimination  of  sugar  conditioned  by  the 
administration  of  protein,  depends  on  the  direct  formation  of  sugar  from 
protein  was  discussed  very  energetically,  especially  through  the  numerous 
objections  of  Ffiuger,  until  Luthje  ascertained  that  after  abundant  adminis- 
tration of  casein  the  total  amount  of  the  excreted  sugar  far  exceeds  the  pos- 
sible amount  of  stored  glycogen.  The  administration  of  fat  does  not  increase 
the  excretion  of  sugar,  yet  it  is  to  be  considered  that  as  a  result  of  the  absence 
of  pancreatic  juice,  fat  is  very  poorly  absorbed.  On  the  simultaneous  ad- 
ministration of  pancreatin  we  have  seen,  however,  in  individual  experiments 
appreciable,  although  only  transitory  increase  in  the  D:N  quotient  (to  7). 

In  addition  to  the  glycosuria  there  exists  polyuria  and  ketonuria.  The 
occurrence  of  the  latter  is  combated  by  many  authors,  although  the  experi- 
ments of  Emhden  and  Lattes  let  it  be  expected  that  in  the  pancreas-diabetic 
dog  there  exists  a  predisposition  to  ketonuria.  If  the  blood  of  normal  cattle 
was  allowed  to  flow  through  the  liver  of  a  pancreasless  dog,  there  was  found 
as  great  an  amount  of  diacetic  acid  as  the  liver  of  normal  animals  lets  be 
produced  only  on  the  addition  of  the  strongest  acetone  formers.  Allard 
saw  in  addition  to  this,  in  pancreasless  dogs,  the  occurrence  of  a  not  inap- 
preciable amount  of  diacetic  acid  and  betaoxybutyric  acid,  especially  when 
pieces  of  pancreas  were  placed  under  the  skin  of  the  abdomen  and  only  later 
extirpated;  when  therefore  the  development  of  the  diabetic  disturbance  of 
metabolism  was  retarded.  In  such  animals  ketonuria  then  develops  rather 
rapidly  and  eventually  leads  to  coma. 

Also  the  protein  metabolism  in  pancreatic  diabetes  shows  definite  dis- 
turbances. Already  Minkowski  had  shown  that  after  removal  of  the  pan- 
creas there  occurs  an  increase  of  the  protein  decomposition.  In  collaboration 
with  Grote  and  Staehelin,  I  showed  that  this  increase  is  constant  and  its 
intensity  conformable  to  law.  The  hunger  protein  exchange  after  complete 
extirpation  attains  to  three  or  three  and  a  half  times  the  hunger  protein  ex- 
change before  the  extirpation.  Mohr  found  less  values;  however,  Eppinger, 
Rudinger,  and  /,  in  the  later  investigations  confirmed  our  former  statements. 

Also  the  excretion  of  salt  is  appreciably  increased,  according  to  the  in- 
vestigations of  Whitney  and  myself. 

Finally  the  respiratory  metabolism  is  essentially  increased,  according 
to  the  investigations  of  Grote,  Staehelin  and  me,  and  of  Mohr.  Our  investiga- 
tions were  carried  out  in  Jaquet's  respiratory  apparatus.  iVlready  the  ap- 
preciable increase  of  the  protein  destruction  would  lead  one  to  expect  an 
increase  of  the  caloric  production,  on  account  of  the  specific  dynamic  energy 
of  protein.  According  to  our  investigations,  however,  the  increase  of  the 
exchange  (about  42  per  cent,  in  the  experiments  not  complicated  with  fever) 


5o6  DISEASES    OF    THE    IXSULAR    APPARATUS    OF    THE    PANXREAS 

was  higher  than  could  be  calculated  from  the  destruction  of  albumin.  An 
increased  exchange  might  be  anticipated  also  from  the  rapid  losses  of  body 
weight,  such  as  were  ascertained  in  the  later  experiments  I  carried  out  with 
Eppinger  and  Riidinger. 

For  the  reason  that  bodies  very  rich  in  oxygen  (sugar  and  ketone  bodies) 
are  excreted,  the  respiratory  quotient  is  very  low.  In  our  experiments  it 
averaged  about  0.73. 

In  the  pancreasless  dog  the  excitability  of  certain  sympathetic  nerves  is 
increased.  O.  Lowi  showed  that  the  instillation  of  atropine  into  the  eye  of 
a  pancreasless  dog  would  produce  mydriasis,  a  stimulus  that  had  been  below 
the  threshold  thus  becoming  operative.  With  this  agrees  the  fact  that  sub- 
cutaneous or  subperitoneal  injection  of  adrenalin,  increases,  according  to 
Eppinger,  Rudinger,  and  my  experiments,  the  D :  X  quotient.  The  amounts 
of  sugar  that  raised  the  quotient  to  more  than  2.8  were  greater  than  those 
which  under  like  conditions  could  be  obtained  by  the  injection  of  adrenalin 
into  normal  fasting  dogs.  Therefore  the  glycosuric  action  of  adrenalin  in 
pancreasless  dogs  is  increased.  As  these  experiments  with  adrenalin  were 
undertaken  at  the  height  of  the  metabolic  disturbance,  therefore  at  a  time 
when  the  glycogen  constituent  was  already  reduced  to  a  minimal,  it  may  be 
supposed  that  this  increase  is  brought  about,  not  only  through  the  increased 
consumption  of  glycogen,  or  through  a  washing-out  of  circulating  sugar,  but 
also  through  an  increased  formation  of  sugar. 

Then,  too,  other  ductless  glands  influence  the  intensity  of  the  pancreatic 
diabetes.  The  experiments  on  simultaneous  extirpation  of  the  thyroid  gland 
or  the  parathyroid  glands  [together  with  the  pancreas]  show  this.  It  is 
known  that  after  thyroid  extirpation  the  hunger  protein  exchange  is  lowered. 
When  the  pancreas  is  simultaneously  extirpated  the  hunger  protein  exchange 
is  about  three  to  three  and  one-half  times  that  of  a  thyroidectomized  dog 
the  same  size,  is  therefore  absolutely  lower  than  after  extirpation  of  the  pan- 
creas alone.  The  excretion  of  sugar  is,  however,  the  same,  so  that  the 
quotient  of  dextrose  to  nitrogen  (D :  N)  is  higher.  In  experiments  in  which, 
together  with  the  pancreas,  a  large  part  of  the  parathyroid  glands  was 
extirpated,  we  found  further  that  the  intensity  of  the  diabetes  was  essentially 
increased.  We  observed  quotients  of  3.6,  although  the  hunger  protein 
destruction  (in  relation  to  the  body  weight)  was  greater  than  was  to  have  been 
expected  in  dogs  of  the  same  size  after  extirpation  of  the  pancreas  alone. 
Further,  worthy  of  mention  is  the  statement  of  Zi'ilzer  that  in  an  experiment 
on  a  dog  in  which  the  pancreas  was  extirpated  and  simultaneously  the  renal 
vein  was  ligated,  the  intensity  of  the  excretion  of  sugar  was  very  slight  and 
transitory. 

We  shall  now  enter  further  into  the  question  as  to  hoic  we  may  explain 
the  occurrence  of  glycosuria  after  extirpation  of  the  pancreas,  or  the  regula- 
tory injluence  of  the  pancreas  on  sugar  metabolism  under  normal  relations. 


DIABETES    AFTER   EXTIRPATION    OF    THE    PANCREAS  507 

It  is  generally  recognized  that  in  the  present  state  of  our  knowledge,  the  as- 
sumption of  an  internal  secretion  of  the  pancreas  is  not  to  be  avoided. 
Opinions  of  former  authors,  that  the  irritation  or  injuries  to  the  sympathetic 
nerve  plexuses  in  the  course  of  the  severe  operations  determined  the  glyco- 
suria, are  contradicted  by  the  transplantation  experiments  of  Minkowski 
and  Hedon.  If  the  part  of  the  pancreas  lying  in  the  mesentery  of  the  duo- 
denum is  transplanted  with  its  vascular  peduncle,  under  the  skin,  and  later 
the  rest  of  the  pancreas  removed,  diabetes  does  not  occur.  A  minimal 
[operative]  attack  then  suffices  to  remove  the  transplanted  piece  and  to  call 
forth  a  diabetes  in  its  fullest  intensity.  That  the  presence  of  pancreatic 
juice  in  the  intestine  is  not  necessary  for  the  normal  course  of  the  carbohy- 
drate metabolism  is  readily  seen  in  the  fact  that  administration  of  pancreatin 
essentially  improves  the  absorptive  disturbances,  but  rather  increases  the 
intensity  of  the  excretion  of  sugar. 

The  experiments  detailed  lead  us  to  assume,  as  alrea.dy  mentioned,  an 
inner  secretion  of  the  pancreas.  We  have  not  as  yet  succeeded,  however,  in 
isolating  the  internal  secretion  and  defining  it  chemically.  We  are  not  even 
certain  as  to  the  path  of  the  giving  off  of  the  same.  Biedl  showed  in  his 
interesting  experiments  on  dogs  that  after  leading  off  the  lymph  of  the  tho- 
racic duct  to  the  exterior,  glycosuria  can  occur.  Biedl  concluded  from  that 
that  the  inner  secretion  of  the  pancreas  is  carried  off  by  the  lymph.  Later 
Biedl  and  Ojfer  stated  that  adrenalin  glycosuria  can  be  prevented  by  the  simul- 
taneous injection  of  duct  lymph.  If  the  internal  secretion  of  the  pancreas 
were  carried  off  by  the  lymph  we  would  expect  that  on  the  administration  of 
the  lymph  of  normal  dogs  to  pancreasless  dogs  the  intensity  of  the  metabolic 
disturbances  would  be  essentially  reduced,  or  that  the  excretion  of  sugar 
would  completely  disappear,  at  least  for  some  time.  In  numerous  investiga- 
tions as  to  this  point  we  could  not  find  these  things.  In  large  dogs  that  were 
fed  abundantly  with  carbohydrates,  the  lymph  from  the  thoracic  duct  was 
collected  for  some  hours,  and  this  lymph  administered  to  pancreasless  dogs 
either  subcutaneously  or  by  the  drop-by-drop  method  into  an  exposed  vein, 
without  producing  an  essential  influence  on  the  quotient  of  dextrose  to  nitro- 
gen (D :  N) ,  although  the  experiments  were  conducted  for  hours  only.  When 
Biedl  more  recently  states  that  he  succeeded  in  similar  experiments  in  de- 
pressing the  D:N  ratio  from  1.8  per  cent,  to  1.5-1.2  per  cent.,  it  seems  to  me 
that  the  difference  is  much  too  small  to  decide  as  to  this  important  question. 
Recently  an  attempt  has  been  made  by  Tuckett  to  explain  the  glycosuria  oc- 
curring in  dogs  with  a  lymph  fistula,  by  the  operative  injury  to  the  sympa- 
thetic nerve  in  the  neck  and  also  by  the  narcosis.  This  explanation,  it  seems 
to  me,  in  consideration  of  the  high  percentage  of  sugar  found  by  Biedh  does 
not  appear  satisfactory.  If  the  internal  secretion  of  pancreas  is  not  carried 
off  by  the  lymphatics — I  leave  this  question  open — there  remains  its  trans- 
ference by  the  pancreatic  veins. 


5o8  DISEASES    OF    THE    INSULAR    APPAR.A.TUS    OF    THE    PANCREAS 

We  have  for  this  reason  collected  the  blood  of  the  pancreatic  veins  of 
large  dogs  and  injected  subcutaneously  the  serum  of  pancreasless  dogs. 
Also  in  these  experiments  were  the  results  negative.  V.  Ehrmann  has  carried 
out  the  same  sort  of  experiments  with  similar  negative  results.  Not  much 
can  be  concluded  from  these  experiments.  The  pancreas  is  extraordinarily 
well  vascularized;  it  may  be  that  the  amount  of  blood  collected  in  a  half 
hour  does  not  contain  enough  internal  secretion  to  produce  distinct  evidence. 
It  should  also  be  considered  that  under  normal  relations  the  blood  of  the  pan- 
creatic vein  is  carried  directly  to  the  liver,  whereas  in  our  experiments  it 
entered  directly  into  the  greater  circulation.  Finally  we  should  consider 
the  possibility  that  the  internal  secretion  is  bound  in  the  blood  corpuscles. 
The  excellent  vascularization  of  the  pancreas  may  also  furnish  the  founda- 
tion for  the  fact  that  we  have  not  as  yet  succeeded  in  obtaining  an  extract 
of  the  pancreas  that  is  active  in  influencing  metabolism.  The  relations  here 
seem  to  be  similar  to  those  affecting  the  likewise  well-vascularized  parathy- 
roid glands.  The  pancreas  is  also  in  respect  to  its  internal  secretion  no  stor- 
age gland  as,  for  example,  the  thyroid  is.  Probably  the  internal  secretion 
is  carried  off  as  it  is  formed.  ZiUzer,  acting  on  similar  considerations,  has 
ligated  the  veins  of  the  pancreas,  thus  producing  a  stasis,  and  claims  to  have 
seen  a  favorable  influence  of  the  extract  obtained  from  such  a  gland  on  the 
glycosuria  of  pancreasless  dogs  and  on  the  ketonuria  of  human  diabetes.  It 
is  true  that  the  statements  of  Zidzer  are  not  very  convincing.  The  results 
in  pancreasless  dogs  are  very  slight,  and  on  the  injection  of  the  extracts  into 
human  beings  shiverings  are  produced  that  influence  the  metabolism  in  a 
non-negligible  way. 

The  question  as  to  which  tissue  element  of  the  pancreas  is  to  be  referred 
the  production  of  the  hypothetical  internal  secretion  has,  since  the  discovery 
of  the  islands,  been  much  discussed,  especially  with  respect  to  human  dia- 
betes. I  regard  it  as  suitable  to  consider  quite  separately  the  results  ob- 
tained in  animal  experimentation,  as  much  speaks  for  the  assumption  that 
human  diabetes  is  not  of  a  single  nature  and  as  the  disturbances  of  absorp- 
tion, observed  after  shutting-oft'  of  the  pancreatic  juice  in  the  animals  ex- 
perimented on  seem  to  deviate  in  many  respects  from  those  in  man.  Soon 
after  the  discovery  of  Langerhans'  islands  the  view  was  expressed  that  these 
pictures,  which  in  their  histological  structure  show  a  certain  similarity  to 
certain  ductless  glands,  especially  the  suprarenal  cortex  and  the  parathy- 
roids, produce  the  internal  secretion  of  the  pancreas,  while  the  glandular 
parenchyma  is  concerned  exclusively  with  the  production  of  the  external 
secretion.  The  view  that  was  later  upheld  by  several  authors,  namely,  that 
the  Langerhans'  islands  could  pass  over  into  glandular  parenchyma,  or 
reversely;  I  have  mentioned  this  in  speaking  of  the  anatomy  and  embryology 
of  the  pancreas;  in  which  exposition,  in  consideration  of  all  the  data  as  to 
the  histological  and  embryological  observations,  I  have  accepted  the  views 


DIABETES    AFTER   EXTIRPATION    OF    THE    PANCREAS  509 

of  those  authors  who  ascribe  to  the  insular  apparatus  a  morphological  and 
embryological  independence.  Of  especial  importance  for  the  insular  theory, 
were,  more  recently,  experiments  that  make  a  functional  independence  in  high 
degree  possible. 

Already  Katz  and  Winkler  had  made  the  observation  that  after  ligation  of  a  larger  ex- 
cretory duct  the  islands  last  for  a  while,  while  the  glandular  parenchyma  in  the  part  of  the 
pancreas  affected  goes  to  pieces.  The  general  attention  was  first,  however,  attracted  to  this 
subject  by  the  mutually  independent  observations  of  v.  Ssoholew  and  Schidze.  Schulze 
ligated  in  guinea-pigs  a  large  lobe  of  the  pancreas  and  found  that  even  after  eighty  days  the 
islands  were  retained,  while  in  the  sclerotic  tissue  were  found  only  traces  of  the  acini. 
Furthermore,  it  should  be  mentioned  that  according  to  Schulze' s  investigation  the  islands 
undergo  no  alteration  during  fasting,  while  the  pancreatic  acini  show  alterations  con- 
ditioned by  the  reduced  function.  Schulze  came  to  the  conclusion  that  the  islands  are  en- 
tirely independent  structures.  Ssobolew  experimented  in  rabbits,  cats,  and  dogs.  The 
results  in  rabbits  were  the  clearest.  The  pancreas  in  rabbits,  which  lies  flattened-out 
between  the  two  layers  of  the  mesentery  possesses  one  excretory  duct  only.  When  this  is 
ligated  the  pancreas  shrinks  markedly,  owing  to  atrophy  of  the  glandular  parenchyma.  It 
is  true  that  Ssobolew  found,  between  the  thirtieth  and  the  one  hundred  and  twentieth  day 
after  the  operation,  slight  sclerotic  alterations  of  the  islands  in  their  clump  of  sclerotic  tis- 
sue, but  later  the  islands  partially  recovered;  and  they  were  retained  even  four  hundred 
days  after  the  operation.  They  also  survived  after  analogous  operations  in  dogs  and  cats. 
In  dogs,  Ssobolew  found  the  atrophy  of  the  glandular  tissue  less  marked,  as  he  supposes 
that  it  forms  new  excretory  ducts.  Tiberii  found,  after  ligation  of  the  excretory  duct  in 
rabbits,  at  first  increased  formation  of  zymogen-granules  in  the  acini,  that  he  regarded  as 
hypersecretion,  then'hyposecretion,  and  finally  complete  cessation  of  granule  formation. 
Later  slight  regeneration  of  the  excretory  duct  made  its  appearance.  In  later  investiga- 
tions Tiberti  found  that  the  great  part  of  the  acini  disappeared,  and  that  pictures 
remain  behind  whose  significance  as  remaining  islands  is  not  clear.  In  two  rabbits, 
Tiberti  found  slight  glycosuria  five  months  after  the  operation.  In  dogs,  according  to 
Tiberti's  investigations,  the  sclerosis  of  the  pancreas  is  less  distinct  than  in  rabbits,  as 
islands  as  well  as  acini  are  in  part  retained. 

Visentini  ligated  the  excretory  ducts  of  the  pancreas  in  twenty-four  dogs;  he  examined 
the  pancreas  two  hundred  and  twelve  days  after  the  operation  and  found  a  gradually  pro- 
gressing sclerosis.  Even  one  hundred  and  twenty  days  after  the  operation  individual 
gland-lobules  were  found;  in  two  experiments  after  two  hundred  and  sixty  and  two  hundred 
and  twelve  days  (respectively)  the  glandular  tissue  had  entirely  gone  to  pieces.  In  the 
dog  that  survived  two  hundred  and  twelve  days  there  was  found  a  slight  glycosuria. 

Sauerbeck  found  after  ligation  of  the  excretory  duct  in  rabbits  gradually  progressing 
sclerosis  of  the  glandular  parenchyma,  the  islands  as  in  the  investigations  of  Ssobolew 
showed  transitory  damages  to  their  structure,  owing  to  the  sclerosing  process.  In 
this  stage,  Sauerbeck,  in  agreement  with  the  older  experiments  of  Hedon  often  observed 
glycosuria,  sometimes  considerable;  in  later  stages  the  islands  again  showed  their  normal 
structure,  and  then  no  glycosuria  existed.  Lombroso  found  in  forty-one  pancreases  of  dogs 
that  the  ligation  of  the  pancreatic  duct  did  not  lead  unconditionally  to  sclerosis.  Islands 
as  well  as  acini  could  be  in  part  retained. 

In  ligation  of  the  duct  in  rabbits,  Lombroso  and  Sacerdote  found  that  the  islands  were 
indeed  retained,  but  that  their  number  and  size  were  diminished. 

Finally  we  should  mention  the  investigations  of  Zuntz  and  Mayer.  After  ligation  of 
the  excretory  duct  of  the  pancreas,  these  authors  found  abundant  retention  of  gland- 
acini  in  certain  cases,  showing  more  or  less  alterations  of  their  structure.     Very  excep- 


5IO  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 

tionally  indeed  did  the  acini  seem  to  have  changed  their  structure.  The  islands  of  Lan- 
gerhans  likewise  showed  alterations  of  structure,  "perhaps  they  seem  smaller,  but  their 
number  does  not  seem  to  have  been  diminished."  A  portion  of  the  island  cells  showed 
alterations  even  already  after  a  few  days;  in  every  case  the  alterations  of  the  islands 
developed  much  more  slowly  than  those  of  the  acini. 

Lomhroso  in  his  works  and  in  a  detailed  review  has  subjected  to  criticism 
the  experiments  just  referred  to,  and  has  come  to  the  conclusion  that  the 
functional  independence  of  the  islands  of  Langerhans  has  not  as  yet  been 
demonstrated.  In  this  conclusion  Lombroso's  own  views  that  to  the  external 
secretion  of  the  pancreas  must  not  be  ascribed  that  freedom  and  independ- 
ence of  the  internal  secretion  that  we  for  a  long  time  tended  to  ascribe  to  it, 
has  had  a  great  influence.  Before  I  discuss  the  question  of  the  independence 
of  the  insular  apparatus,  I  must  enter  first  into  an  account  of  the  disturb- 
ances of  absorption  after  extirpation  of  the  pancreas  or  after  ligation  of  its  duct. 

Already  Abiiinaini,  whom  we  have  to  thank  for  the  fundamental  absorption  e.xperi- 
ments  after  extirpation  of  the  pancreas,  stated  that  it  is  true  after  total  extirpation,  the 
absorption  of  fat  in  the  intestine  almost  completely  ceases,  although  fat-splitting  may  be 
very  good;  that,  however,  the  disturbance  of  absorption  never  reaches  to  this  extreme 
grade  when  a  part  of  the  pancreas  is  left  behind,  even  when  its  connection  with  the  intes- 
tine is  entirely  broken  up.  Also  after  ligation  of  the  excretory  duct  is  the  disturbance  of 
absorption  never  intense.  It  has  been  attempted  to  explain  this  by  the  statement  that  in 
this  case  the  pancreatic  juice  is  in  part  absorbed,  and  reaches  the  intestine  by  way  of  the 
blood-vessels  or  that  the  dogs  with  pancreatic  fistula  lapped  up  the  secretion  that  flowed 
out.     (Sinn,  Hess,  Burckhardt,  d  al.) 

Besides  this  it  is  mentioned  that  in  dogs  there  often  occur  accessory  pancreases,  and 
that  in  such  cases  therefore  the  complete  cutling-off  of  the  pancreatic  juice  from  the  intes- 
tine isverydiflicult.  Sinn,  a.n(\Hess  found  almost  regularly  in  dogs  a  third  excretory  duct 
of  the  pancreas.  According  to  these  authors  the  ligation  of  all  ducts  is  especially  difficult 
intra  vitam.  When  it  really  succeeds,  there  occurs  within  some  weeks  an  almost  complete 
necrosis  of  the  pancreatic  tissue.  In  these  cases  ^^55,  and  5/«h,  found  no  diabetes,  inmost 
cases,  however,  an  appreciable  temporary  disturbance  of  protein  and  fat  absorption.  In 
some  cases  indeed  the  absorption  was  quite  good.  Lomhroso  in  his  numerous  experi- 
ments has  ascertained  the  following :  The  absorption  of  fat  in  dogs  is  rather  good  when  the 
entire  number  of  ducts  are  ligated,  or  when  after  a  part  of  the  pancreas  has  been  trans- 
planted and  a  fistula  from  this  to  the  outside  has  been  made,  the  other  part  of  the  pancreas 
has  been  extirpated.  This  also  occurred,  according  to  Lomhroso,  when  the  re-ingestion  of 
the  secretion  was  entirely  prevented. 

In  an  experiment  carried  out  in  Minkowski's  laboratory  the  disturbance  of  the  absorp- 
tion of  fat  was  indeed  not  inappreciable  (up  to  60  per  cent.).  When  later  the  vascular 
nervous  pedicle  of  the  transplanted  part  of  the  pancreas  was  ligated  and  cut,  a  transitory 
glycosuria  occurred,  and  the  fistula  secreted  further.  Only  after  extirpation  of  the  remain- 
ing part  of  the  pancreas  did  the  diabetes  and  the  disturbance  in  fat  absorption  reach  its  full 
height.  In  a  second  analogous  experiment,  glycosuria  was  present  from  the  first,  but  the 
disturbance  of  absorption  in  this  case  was  less  (38.7  per  cent.).  Lomhroso  further  showed 
that  bile,  saliva,  and  intestinal  juice  show  no  alterations  in  their  enzymatic  characteristic, 
and  that  therefore  an  excretion  of  absorbed  pancreatic  juice  into  the  intestine  was  there- 
fore improbable.  This  was  also  confirmed  by  Zuntz  and  Mayer.  Lomhroso  concluded 
from  his  experiments  that  the  influence  of  the  pancreas  on  the  absorption  of  fat  was  also 


DIABETES    AFTER   EXTIRPATION    OF    THE    PANCREAS  51I 

conditioned  through  an  internal  secretion.  Fleckseder  has  instituted  analogous  experi- 
ments. He  observed  that  the  using  up  of  fat  and  albumin  is  somewhat  diminished  in 
the  fistula  animals,  whether  the  secretion  is  let  flow  free  from  the  fistula,  or  is  let  stagnate, 
whether  it  is  re-ingested  or  not.  Very  interesting  is  an  experiment  of  Fleckseder' s  in  which 
gradually,  through  increasing  sclerosis  of  the  piece  of  pancreas  left  behind,  a  diabetes 
developed  to  full  height,  the  secretion  from  the  fistula  stopped,  but  the  absorption  of  fat 
was,  however,  better  than  before. 

Lombroso  in  his  review  has,  as  before  mentioned,  doubted  the  significance 
of  the  ligation  experiments  for  the  functional  independence  of  the  pancreas. 
He  uses  the  just  mentioned  disturbances  of  absorption  in  a  like  sense,  and 
comes  to  the  conclusion  that  islands  as  well  as  gland  parenchyma  take  part 
in  the  production  of  the  external  secretion  of  the  pancreas,  and  that  this  is  of 
importance  for  the  carbohydrate  metabolism  as  well  as  for  fat  absorption. 

The  amalgamation  of  both  questions  seem  to  be  rather  unhappy.  From 
the  experiments  just  cited  it  seems  that  the  two  disturbances  do  not  run  a 
parallel  course  throughout.  Thus  we  found,  for  instance,  in  one  of  Lombroso' s 
experiments  relatively  good  absorption  in  spite  of  existing  glycosuria,  and  in 
an  experiment  of  Fleckseder^ s  right  good  absorption  in  spite  of  a  fully  de- 
veloped diabetes.  On  the  other  hand  we  find  in  an  experiment  of  Lombroso' s 
a  not  inappreciable  disturbance  of  absorption  in  spite  of  absence  of  a  dis- 
turbance in  carbohydrate  metabolism.  So  much  is  therefore  certain  that,  if 
an  internal  secretion  of  the  pancreas  actually  essentially  influences  the  absorption 
of  fat,  it  is  not  identical  with  the  pancreatic  hormone  regulating  carbohydrate 
metabolism.  As  we  shall  see  later,  the  same  is  true  of  the  observations  on 
human  diabetes. 

In  men  the  relations  are  on  the  whole  much  clearer  than  in  the  dog.  Here 
we  find  cases  with  severe  lethal  diabetes  and  high-grade  isolated  disease  of 
the  insular  apparatus;  in  spite  of  this,  in  these  cases  the  characteristic,  not-to- 
be-overlooked,  fat  stools  are  absent.  On  the  other  hand,  when  the  pancreatic 
juice  is  completely  cut  off,  fat  stools  occur,  as  we  shall  see  later,  which  im- 
prove considerably  on  the  administration  of  pancreatin.  Characteristic  of 
these  pancreas  stools  in  men  is  the  deficiency  of  the  splitting  of  neutral  fat, 
whereas  in  the  dog,  according  to  the  statements  of  all  investigators  the  split- 
ting of  fats  is  not  essentially  disturbed  even  after  the  total  extirpation  of  the 
pancreas. 

In  reviewing  the  information  at  hand  up  to  the  present  time,  we  find, 
according  to  my  opinion  that  we  can  thus  far  say  with  certainty,  only  that 
the  absorptive  activity  of  the  intestinal  mucosa  is  somehow  influenced  by 
the  pancreas  even  when  the  pancreas  is  entirely  separated  from  the  intestine, 
that,  however,  this  influence  is  independent  within  wide  limits  of  that  oj  the 
carbohydrate  metabolism  through  the  pancreatic  hormone.  At  all  events,  I  do 
not  regard  it  as  proper  that  these  not  at  all  negligible  relations  should  be  used 
as  a  basis  against  the  teaching  of  the  functional  independence  of  the  glandular 


512  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

and  the  insular  apparatus.  For  this  independence  speak  the  known  trans- 
plantation experiments  of  Minkowski,  Gley,  Thiroloix  and  Hedon.  When  we 
pass  these  in  review  from  the  standpoints  above  mentioned,  we  see  that  the 
production  of  pancreatic  juice,  therefore  the  function  of  the  glandular 
parenchyma,  is  quite  independent  of  the  disturbance  in  carbohydrate  me- 
tabolism. The  glandular  parenchyma  of  the  transplanted  piece  may  atrophy, 
the  secretion  from  the  fistula  may  stop  flowing,  and  yet  the  diabetes  remain 
absent.  Only  after  extirpation  of  the  sclerotic  piece  (with  the  retained 
islands)  does  the  diabetes  set  in.  On  the  other  hand,  there  is  known  the  ex- 
periments of  Thiroloix  in  which  diabetes  set  in  after  the  transplantation,  in 
which  case  therefore  the  islands  probably  suffered  harm,  while  the  secretion 
continued  to  flow  from  the  fistula. 

I  do  not  subscribe  to  the  critical  remarks  of  Lomhroso  directed  against  the 
remaining  refractory  of  the  insular  apparatus  after  duct  ligation.  It  seems 
to  be  intelligible  that  the  chronic  inflammatory  processes  that  occur  after 
ligation  of  the  duct,  may  under  certain  circumstances  damage  also  the  insular 
apparatus  and  on  account  of  this  lead  transitorily  to  glycosuria.  There  is 
no  longer  doubt  as  to  the  fact,  now  communicated  from  all  sides,  that  also  a 
long  time  after  the  ligation  of  the  duct  the  entire  glandular  apparatus  becomes 
sclerotic,  the  insular  apparatus  remains  entirely  or  largely  retained,  and  that 
on  this  account  disturbances  in  carbohydrate  metabolism  remain  absent. 
The  experiments  on  pigeons  that  Lomhroso  quotes  as  support  of  his  position 
are  not  convincing.  In  these  experiments  although  the  insular  apparatus 
was  apparently  markedly  damaged,  the  glycosuria  remained  absent.  As 
Biedl  has  already  pointed  out,  however,  in  many  species  of  birds,  the  total 
extirpation  of  the  pancreas  does  not  lead  to  glycosuria,  but  only  to  hypergly- 
cemia. The  experiments  on  transplantation  of  the  pancreas  and  the  institu- 
tion of  a  pancreatic  fistula  seem  to  me  to  be  especially  poorly  adapted  for  the 
decision  of  this  question.  If  the  healing  follows  by  primary  intention  the 
carbohydrate  metabolism  and  also  the  insular  apparatus  do  not  alter.  If, 
however,  infection  occurs  and  on  account  of  this  infection  sclerosis  of  the 
pancreas  sets  in,  naturally  the  insular  apparatus  can  also  be  damaged,  and 
often  it  would  be  very  hard  to  estimate  in  such  an  altered  pancreas  the 
functional  integrity  of  the  tissue  constituents  still  present.  I  have  carried 
on  some  experiments  that  in  spite  of  the  unfavorable  relations  seem  to  me  to 
point  to  the  functional  independence  of  the  two  apparati. 

Zuntz  and  Mayer  found  in  their  pretty  experiments  that  the  ligation  of 
the  excretory  duct  led  in  the  dog  first  to  a  more  or  less  well-expressed  loss  of 
body  weight.  Mostly  the  dogs  rapidly  regain  their  body  weight  and  then 
live  from  then  on  like  normal  dogs.  In  other  cases,  however,  the  body  weight 
falls  still  further,  the  emaciation  terminating  in  death.  Now  Zuntz  and 
Mayer  found  an  almost  complete  disappearance  of  the  glandular  acini  in 
these  dogs,  while  in  the  dogs  that  recovered  the  disappearance  of  the  glandu- 


DIABETES    AFTER    EXTIRPATION    OF    THE    PANCREAS  513 

lar  parenchyma  proceeds  much  more  slowly.  Zuntz  and  Mayer  conclude 
from  this  that  in  addition  to  the  production  of  the  pancreatic  juice  and,  of  the 
still  hypothetical  hormone  regulating  carbohydrate  metabolism  the  pancreas 
has  still  another  function,  by  which  it  becomes  concerned  with  general  me- 
tabolism. Cannot  fat  necroses,  that  are  known  to  be  difficult  to  avoid  in  the 
operation  on  the  pancreas,  have  played  a  part  in  the  sudden  death  of  the  dogs? 

I  should  like  to  summarize  the  results  of  the  experimental  investigation 
up  to  the  present  in  the  following  propositions.  There  is  probably  produced 
from  the  insular  apparatus  of  the  pancreas  a  hormone  that  is  given  principally 
to  the  venous  blood  and  carried  to  the  liver.  When  this  hormone  is  absent, 
marked  excretion  of  sugar  and  disturbance  of  glycogenesis  occurs.  Further, 
there  occurs  elimination  of  ketone  bodies.  The  decomposition  of  protein 
and  the  excretion  of  salts,  and  again  the  production  of  calories  is  highly 
increased,  and  finally  there  occurs  an  increased  excitability  of  the  sympa- 
thetic nerves. 

According  to  my  view,  there  speaks  for  a  disturbance  of  glycogenesis,  in 
addition  to  the  marked  poverty  in  glycogen,  especially  the  fact  that  we  have 
in  partial  extirpation  of  the  pancreas  {Sandmeyer's  diabetes)  the  occurrence 
of  a  glycosuria  only  on  alimentary  overfeeding.  In  the  severest  forms, 
at  the  height  of  the  metabolic  disturbance  the  glycogen  formation  in  the 
liver  seems  markedly  reduced.  For  this  speaks  the  observation,  as  already 
Minkowski  found,  that  the  administration  of  dextrose  raises  the  sugar- 
elimination  to  about  the  amount  administered,  and  also  the  demonstration 
furnished  hy  Grote,  Staehelin  and  myself,  that  administration  of  sugar  does  not 
increase  the  respiratory  quotient.  That  glycogen  formation  is  not  entirely 
in  abeyance  is  spoken  for,  among  other  circumstances,  by  the  fact  that  we 
may  still  obta,in  it  on  the  administration  of  levulose. 

In  my  opinion  there  speaks  for  an  overproduction  of  sugar  the  fact  that 
also  in  fasting,  when  the  alimentary  influences  are  entirely  ruled  out,  sugar 
production  proceeds  in  the  liver  with  the  intensity  that  it  does. 

Finally  there  remains  for  discussion  the  question  as  to  whether  the  over- 
production in  the  liver  is  alone  the  cause  of  the  sugar  elimination,  or  whether 
also  the  combustion  of  sugar  in  pancreatic  diabetes  is  diminished  or  increased. 
An  attempt  has  been  made  to  reach  nearer  the  solution  of  this  question  by 
investigating  whether  muscular  work  will  reduce  the  elimination  of  sugar. 
The  basic  investigations  of  Seo  have  shown  that  after  incomplete  extirpation 
of  the  pancreas  sugar  elimination  as  well  as  the  quotient  D :  N  diminishes 
under  the  influence  of  muscular  work.  After  complete  extirpation  of  the 
pancreas  no  such  diminution  occurs.  If  a  shorter  period  be  investigated, 
there  rather  occurs  an  increase  in  the  quotient.  If  in  such  an  animal  the 
elimination  of  sugar  at  a  later  stage  has  started  to  fall,  there  occurs  as  a  result 
of  muscular  work  an  increase  in  the  quotient  even  above  that  regarded  as 
the  maximal  boundary.     From  this  Seo  concludes  that  the  increase  in  the 

33 


514  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

consumption  of  sugar  on  account  of  muscular  work  is  only  possible  when 
pancreatic  tissue  is  still  present  in  the  organism.  This  conclusion  is  not, 
however,  very  convincing,  v.  Xoorden  explained  analogous  observation  in 
human  diabetes  by  the  fact  that  as  a  consequence  of  oversensitiveness  of 
the  sugar-forming  apparatus  the  steady  appeal  of  which  to  the  liver  for 
much  sugar  during  muscular  work  is  answered  in  an  excessive  manner. 

The  fact  that  the  respiratory  quotient  after  total  extirpation  of  the  pan- 
creas is  maintained  at  a  very  low  level,  and,  as  previously  mentioned, 
remains  at  this  level  in  spite  of  administration  of  carbohydrates,  was  formerly 
regarded  as  a  chief  argument  for  the  disturbance  of  carbohydrate  combustion. 
V.  Noorden  mentions,  however,  that  it  has  not  as  yet  been  shown  that  the 
substance  that  undergoes  combustion  in  muscle  is  not  a  sugar.  What  it  has 
been  shown  is  only  that  the  excretory  product  is  not  a  nutritional  carbohy- 
drate; it  may,  however,  be  a  fat. 

Also  other  authors  express  themselves  as  against  a  disturbance  in  sugar 
combustion.  CJiauveau  and  Kaufman  investigated  the  sugar  contents  in 
the  arterial  and  venous  blood  of  pancreasless  dogs,  and  found  that  of  the 
arterial  blood  higher.  Investigations  on  the  "sugar  puncture''  hypergly- 
cemia yielded  the  same  result.  Forges  and  Salomon  found  in  their  experiments 
that  on  exclusion  of  the  entire  portion  of  the  body  lying  below  the  diaphragm, 
the  respiratory  quotient  in  the  pancreasless  dog  rose  as  high  or  as  even  higher 
than  in  normal  animals  under  the  same  conditions.  As  the  combustion 
under  these  conditions  takes  place  chiefly  in  the  muscles,  they  assume  that 
after  removal  of  the  pancreas,  the  muscles  are  in  a  condition  to  burn  up  sugar. 

Recently  Knouthon  and  Starling  have  again  entered  the  lists  for  a  dis- 
turbance of  the  sugar  combustion  in  the  pancreasless  dog.  If  a  heart-lung 
preparation  of  a  normal  dog  is  transfused  with  normal  blood,  there  occurs  a 
strong  consumption  of  sugar.  If,  however,  the  heart-lung  preparation  of  a 
pancreasless  dog  is  transfused  with  the  normal  blood,  the  consumption  of 
sugar  straightway  becomes  o.  If  dealbuminized  pancreas  extract  be  ad- 
ded to  this  blood,  consumption  of  sugar  reappears.  Knoutlwn  and  Starling 
conclude  from  this  that  tissue  and  blood  contain  a  substance  ordinarily 
coming  from  the  pancreas  that  is  necessary  for  the  sugar  consumption  in  the 
tissues. 

The  experiments  of  Knouthon  and  Starling  may  be  interpreted  in  two 
ways:  Either  in  normal  dogs  the  sugar  is  burned,  or  it  is  polymerized  and 
assimilated.  According  to  the  interesting  experiments  of  Levene  and  Meyer 
the  latter  is  not  at  all  unlikely.  For  these  authors  showed  that  through 
the  combined  action  of  muscle-plasma  and  pancreas  extract,  the  power  of 
reduction  of  a  sugar  solution  becomes  reduced,  but  may  be  regained  on 
cooking  with  acids. 

The  experiments  also  make  necessary  a  revision  of  the  important  investi- 
gations of  Lepine  on  glycolysis. 


EXPERIMENTAL    XERVOUS    DI.AJBETES  515 

It  is  very  unlikely  that  the  combustion  of  sugar  in  the  pancreasless  dog 
ceases  entirely.  It  must  not  be  forgotten,  that  very  intense  grades  of  glyco- 
suria occur  not  only  in  human  beings,  but  that  forms  of  diabetes  may  also 
be  produced  in  dogs,  that  are  associated  with  a  more  intense  elimination  of 
sugar  than  is  the  case  in  pancreas  diabetes.  I  refer  to  investigations  of  Lusk 
on  phloridzin  diabetes,  in  which  the  quotient  3.6  was  regularly  attained. 
x\lso  in  our  investigations  on  simultaneous  extirpation  of  the  pancreas  and 
thyroid  gland,  and  especially  of  pancreas  and  parathyroid  glands  were  the 
quotients  high.  Therefore  in  ordinary  pancreatic  diabetes  it  must  either  be 
that  less  sugar  is  formed,  or  that  sugar  is  still  consumed. 

If  we  adopt  the  standpoint  that  the  combustion  of  sugar  in  the  muscles 
is  only  possible  after  preceding  assimilation,  the  experiments  of  Starling 
would  show  that  the  glycogenesis  in  the  muscles  and  probably  also  in  other 
cells  that  otherwise  contain  glycogen  is,  "without  the  pancreatic  hormone, 
highly  reduced.  A  certain  grade  of  glycogenesis  is  always  found  remaining 
in  the  pancreatic  diabetic  dog.  as  already  mentioned.  If  we  assume  that  in 
the  experiments  of  Forges  and  Saloman  that  only  the  carbohydrates  just 
assimilated  is  consumed  to  the  last  traces,  we  may  readily  bring  it  in  harmony 
with  the  assumption  that  the  assimilation  of  carbohydrates  in  the  muscles  of 
pancreasless  dogs  is  diminished.  It  seems  to  me  therefore  that  the  two  series 
of  experiments  do  not  unconditionally  contradict  each  other,  if  the  fact  is 
emphasized  that  in  the  pancreasless  dog  the  formation  of  glycogen  is  dis- 
turbed not  only  in  the  muscles  but  also  in  the  liver. 

It  is  very  hard  to  explain  the  enormous  increase  of  the  protein  decomposi- 
tion, the  salt  elimination,  and  especially  also  the  caloric  production,  in  the 
dog  with  pancreatic  diabetes.  I  shall  return  to  this  in  the  theoretical  con- 
siderations, later  on. 

I  might  summarize  what  I  have  just  detailed  in  the  following  hypo- 
thesis: The  pancreatic  hormone  is  an  exquisitely  assimilatory  hormone, 
and  governs  glycogenesis  in  the  liver  and  muscles.  In  the  light  grades  of 
insufLciency  the  disturbance  in  carbohydrate  metabolism  occurs  only  when 
there  are  instituted  great  demands  on  glycogenesis  in  the  liver  {alimentary  over- 
loading with  carbohydrates).  In  the  severer  disturbances  there  occurs,  in  addi- 
tion to  the  disturbance  in  anabolism .  a  marked  increase  in  catabolic  processes 
and  thereby  a  faulty  decomposition  of  higJier  and  lower  fatty  acids  (ketonuria). 

B.  Experimental  Nervous  Diabetes 

The  experimental  nervous  diabetes  will  be  mentioned  here  only  briefly. 
Many  important  facts  have  already  been  mentioned  in  the  chapter  on  the 
suprarenals.  We  have  to  thank  Claude  Bernard  for  the  fundamental  ex- 
periment. A  puncture  at  a  definite  place  in  the  fourth  ventricle  leads  in 
many  animals  to  a  glycosuria  lasting  several  hours.     Recently  Aschner  has 


5l6  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

shown  that  a  similar  sugar  center  lies  also  further  centrally,  in  the  subtha- 
lamic region.  In  sugar  puncture  the  stimulus  travels  over  the  paths  of  the 
sympathetic,  and  leads  to  an  unburdening  of  liver  glycogen  and  to  hypergly- 
cemia. If  the  conduction  is  interrupted  in  the  spinal  cord  above  the  giving- 
off  of  the  splanchnics,  or  if  the  liver  is  previously  rendered  sugar-free,  as  for 
instance,  by  strychnine,  the  puncture  is  of  no  avail.  Until  up  to  a  few  years 
ago  this  is  as  far  as  the  mechanism  of  sugar  puncture  had  been  explained, 
nor  did  we  know  how  the  impulse  was  carried  over  from  the  splanchnics  to 
the  liver.  The  investigations  of  the  last  few  3'ears  have  shown  that  the  chro- 
maffin tissue  is  to  be  regarded  as  the  governing  de\4ce.  Already  Blum  had 
expressed  the  opinion  that  sugar  puncture  acted  by  way  of  the  suprarenals. 
In  common  with  Eppinger  and  Rudinger,  I  showed  that  in  thyroidless  dogs 
adrenalin  glycosuria  as  well  as  "  sugar  puncture ''  glycosuria  were  not  induced. 
Both  were  therefore  prevented  by  the  same  factor.  Waterman  and  Smith 
found  after  puncture  a  mydriatic  substance  in  the  serum.  But  to-day  we 
must  consider  the  methods  used  by  these  authors  for  the  demonstration  of 
adrenalin  as  insufficient.  A  further  analogy  betw^een  adrenalin  glycosuria 
and  sugar  puncture  lies  in  the  appreciable  hyperemia  of  the  liver  that  occurs 
after  each  procedure,  as  Priestly  and  /  have  pointed  out.  After  each  pro- 
cedure there  occurs  an  increase  in  blood-pressure  (E.  Xeuhauer) .  For  the  con- 
vincing experiment  we  have  to  thank  R.  H.  Kahn.  He  showed  that  after 
sugar  puncture  the  staining  of  the  suprarenals  to  chrome  dyes  as  w^ell  as  the 
pressor  power  of  the  suprarenal  extract  decreases.  If  the  puncture  is  done 
after  previous  section  of  both  splanchnics  the  glycosuria  remains  absent, 
as  is  known,  and  the  staining  of  the  suprarenals  to  chrome  dyes  is  retained. 
It  was  shown  therewith,  in  confirmation  of  the  experiments  of  XisJii,  that 
the  left  splanchnic  supplies  both  suprarenals,  while  the  right  splanchnic  gives 
oft"  fibers  only  to  the  right  suprarenal;  for  on  action  of  the  right  splanchnic 
the  puncture  makes  both  suprarenals  poorer  in  adrenalin,  while  on  section 
of  the  left  splanchnic  only  the  right  suprarenal  suffers  somewhat  in  its  adrena- 
lin contents.  Electrical  stimulation  of  the  splanchnic  (section  of  the  nerves 
and  stimulation  of  the  peripheral  stump)  elicits  glycosuria.  Tschebokraroff 
had  previously  shown  that  the  adrenalin  contents  of  the  blood  of  the  supra- 
renal veins  is  increased  by  electrical  stimulation  of  the  splanchnics. 

Therefore  the  action  of  sugar  puncture  may  be  explained  by  an  afferent 
impulse  conducted  along  the  splanchnics,  -which  leads  to  an  unloading  of  the 
chromaffin.  How  adrenalin  occasions  a  dissemination  of  the  sugar  from  the 
liver  is  not  as  yet  clear.  E.  Neuhauer  thought  that  the  hyperemia  of  the 
liver  was  alone  the  cause  of  the  dissemination  of  glycogen.  I  think,  however, 
that  against  this  speaks  the  fact  that  there  are  agents  that  bring  about  dis- 
tinct hyperemia  of  the  liver  without  producing  glycosuria.  Such  an  action 
has  pituitrinum  infundibulare,  for  instance.  The  hyperemia  of  the  liver 
may,  however,  very  well  favor  the  development  of  a  glycosuric  action,  as  has 


EXPERIMENTAL    NERVOUS    DIABETES  517 

already  been  dealt  with  in  the  chapter  on  the  suprarenals.  We  might  sup- 
pose an  activation  of  the  diastatic  ferment  in  the  liver.  Hofmeister  reports 
recently  that  after  the  puncture,  the  glycogen  for  the  most  part  is  no  longer 
found  in  the  liver-cells,  but  in  the  efferent  lymph  and  blood-vessels.  Zillzer 
first  propounded  the  view  that  adrenalin  and  the  pancreatic  hormone  have  an 
antagonistic  action.  The  poisonous  action  of  adrenalin  would  be  neutralized 
by  the  pancreas  hormone  in  the  liver,  v.  Noorden  expressed  the  view  that 
both  pancreas  and  chromaffin  tissue  influence  the  diastatic  process  in  a  con- 
trary manner — the  pancreas  inhibits,  the  chromaffin  tissue  accelerates  it. 
V.  Fiirth  and  Schwarz  have  taken  justified  exception  to  the  experiment  of 
Zulzer.  A  certain  opposition  in  the  action  of  the  pancreatic  hormone  and  of 
adrenalin  is,  however,  unmistakable.  The  former  works  assimilatorily,  govern- 
ing the  building  up  of  glycogen,  and  the  latter  is  dissimilatory,  occasioning 
melting  down  of  glycogen  and  decomposition  in  sugar.  At  all  events  we  shall 
see  later  that  the  alimentary  factor  governed  by  the  pancreas  and  the 
nervous  factor  working  by  way  of  the  chromaffin  tissue  may  be  highly  inde- 
pendent of  each  other. 

According  to  later  investigations  of  Bernstein  and  myself,  I  might  assume 
that  as  in  the  liver  so  also  in  the  muscular  system  the  same  regulating  powers 
that  govern  assimilation  and  dissimilation  are  opposed  to  each  other.  In  a 
large  series  of  experiments  we  saw  the  respiratory  quotient  rise  in  human  be- 
ings after  the  injection  of  adrenalin  (previously  Roth  and  Fuchs  had  already 
reported  on  two  experiments  on  patients  with  Addison's  disease) .  The  rise 
in  the  respiratory  quotient  may  be  so  appreciable  that  from  it  we  may  infer 
a  combustion  of  an  additional  30-40  gm.  of  sugar  in  the  course  of  from  half 
to  three-quarters  of  an  hour.  As  after  injection  of  adrenalin  there  occurs 
also  an  impoverishment  of  the  muscles  in  glycogen;  I  would  consider  most 
likely  that  under  the  influence  of  adrenafin  the  glycogen  is  everywhere  mobil- 
ized and  burnt^  in  a  precipitate  manner,  whereby  a  greater  part  of  the  sugar 
is  furnished  precipitately  to  the  blood  from  the  liver,  producing  hyper- 
glycemia and  glycosuria.  Now  it  is  very  noteworthy  that  in  severe  cases  of 
diabetes  mellitus,  that  had  been  made  sugar-free,  we  saw  after  injection  of 
adrenafin  considerable  glycosuria,  but  no  rise  in  the  respiratory  quotient. 
Hence  there  is  absent  in  the  severe  diabetic  the  power  to  take  into  combustion 
precipitately  mobilized  sugar;  of  course  the  possibifity  should  be  considered 
that  the  sugar  mobifized  on  account  of  adrenafin  in  the  severe  diabetic  ema- 

1  Such  an  increased  combustion  of  carbohydrate  seems  moreover  to  be  able  to  occur  isolated 
in  the  muscles.  I  refer  to  the  experiments  with  "pituitrinum  glandulare"  already  quoted  in 
the  chapter  on  the  hypophysis,  in  which  there  occurred  a  rise  in  the  respiratory  quotient,  while 
all  other  actions  were  quite  opposed  to  those  of  adrenalin  (lessening  of  the  volume  of  the  liver, 
sinking  of  blood-pressure,  no  rise  in  blood  sugar,  but  more  often  slight  reduction,  and  finally 
reduction  in  the  total  caloric  exchange).  Also  in  two  experiments  on  severe  diabetics  was  there 
a  rise  in  the  respiratory  quotients,  while  the  reduction  of  the  total  gas  exchange,  showed  with 
certainty  that  the  agent  was  active. 


5l8  DISEASES    OF    THE    IXSULAR    APPARATUS    OF    THE    PANCREAS 

nates  not  from  glycogen,  but  from  fat;  in  such  a  case  the  respiratory  quotient 
should,  however,  sink. 

n.  CLINICAL  PARTS 

Although  we  are  informed  as  yet  only  by  hypotheses  as  to  the  intimate 
process  by  which  the  pancreas  enters  into  the  regulation  of  the  carbohydrate 
metabolism,  we  have  no  reason  for  doubting  the  fact  that  the  pancreas  be- 
longs to  the  most  important  regulators  of  the  carbohydrate  metabolism  and 
plays  a  leading  role  in  its  disturbances.  If  now  we  try  to  enter  further  into 
the  question  as  to  what  role  the  pancreas  or  its  inner  secretory  function  plays 
in  human  pathology,  we  find  that  it  is  more  to  our  purpose  to  view  the 
problem  from  two  different  sides.  On  the  one  hand  it  will  be  necessary  to 
pass  in  review  the  clinical  pictures  in  which  gross  anatomical  alterations  of 
the  pancreas  have  been  observed,  and  to  analyze  which  symptoms  of  the 
total  symptom-complex  can  be  referred  eventually  to  the  disturbance  of  the 
internal-secretory  activity.  A  thorough  description  of  these  disease  pictures 
does  not  lie  within  the  province  of  the  task  I  have  set  for  myself,  and  is  also 
not  necessary  for  the  purpose  I  am  striving  for;  yet  it  seems  tome  desirable 
to  delineate  them,  at  least  in  coarse  outlines.  For  as  we  have  already 
mentioned  in  the  consideration  of  the  experimental  physiology,  there  have 
been  attempts  to  bring  many  symptoms  that  were  formerly  referred  to  as 
the  external  secretion  of  the  pancreas  into  connection  with  the  internal 
secretion.  On  the  other  hand  I  shall  draw  the  essential  features  of  the 
metabolic  disturbance  that  we  designate  diabetes  mellitus,  describe  the 
pathologico-anatomical  alterations  found  in  the  condition,  and  discuss  what 
role  the  pancreas  plays  in  it. 

It  will  be  evident  that  there  are  a  number  of  cases  the  analysis  of  which 
we  can  approach  as  well  the  one  way  as  the  other. 

A.  Gross  Anatomical  Disturbances 

An  etiological  classification  of  the  diseases  of  the  pancreas  is  not  possible 
to-day.  As  yet  we  know  far  too  little  in  this  respect.  At  any  rate,  the  role 
played  by  infection  is  important.  This  may  occur  hematogenously,  or  by 
contiguity,  in  which  case  infectious  processes  of  the  neighboring  parts  affect 
the  pancreas;  and  finally  especially  in  gall-stone  aft'ections  {Hirschfeld)  in 
which  infection  reaches  it  from  the  intestines  through  the  ducts.  The  route 
last  mentioned  is  by  far  the  most  frequent.  An  important  role  is  played  by 
diseases  of  the  vessels  of  the  pancreas  and  by  cirrhotic  process  that  depend 
on  the  chronic  action  of  poisons  (alcoholism,  etc.).  Also  trauma  may  come 
into  consideration  as  an  etiological  factor,  especially  in  existing  arterio- 
sclerosis of  the  pancreas.  Further  we  recognize  a  series  of  tumors  of  the 
pancreas  under  which  carcinoma  is  by  far  the  most  common;  further  cyst 
formation,  the  genesis  of  which  mav  be  of  various  nature,  and  finallv  a  con- 


GROSS    ANATOMICAL    DISTURBAXCES  519 

genital  failure  of  development  especially  of  the  insular  apparatus  fsee  genuine 
diabetes). 

An  acute  attack  of  the  function  of  the  entire  pancreas  may  be  observed 
under  circumstances  in  apoplexy  of  the  pancreas  or  in  acute  hemorrhagic 
pancreatitis.  The  first  occurs  chiefly  in  old  corpulent  drunkards  vdth  ad- 
vanced arteriosclerosis.  In  association  with  suddenly  onsetting  abdominal 
pains  there  occurs  distention  of  the  abdomen  in  the  epigastrium,  retention  of 
feces,  vomiting,  and  finally,  with  distinctly  pronounced  manifestations  of 
ileus,  death  in  the  course  of  a  few  hours  or  days.  Section  shows  enormous 
blood  eft'usions  in  the  pancreas,  and  eventually  into  the  abdominal  caAity,  as 
the  consequence  of  hemorrhage  from  the  pancreatic  vessels.  The  course  of 
the  disease  is  for  the  most  part  so  fulminant,  that  glycosuria  mostly  does 
not  occur  even  on  complete  destruction  of  the  pancreas. 

Acute  hemorrhagic  pancreatitis  usually  sets  in  with  acute  gastric  dis- 
turbances after  indefinite  prodromal  s}Tnptoms  that  have  lasted  for  some 
time;  to  the  gastric  disturbances  are  rapidly  added  distention  of  the  epigas- 
trium, A-iolent  pressure  pains  in  the  pangreatic  region  and  high  fever;  either 
death  follows  rapidly  under  the  manifestations  of  acute  ileus  and  perforation 
peritonitis,  or  the  case  comes  to  remissions;  then  usually  the  disease  lasts  a 
longer  time.  Symptoms,  that  depend  on  falling  away  of  function  of  the 
pancreas  are  not  rarely  observed.  In  a  case  that  proceeded  rather  acutely, 
I  found  12  per  cent,  of  sugar  in  the  urine.  In  this  case  the  reduction  of  the 
copper  sulphate  took  place  even  in  the  cold.  An  interesting  case  -^dth  a 
chronic  course  is  described  by  Albu.  In  a  twenty-nine-year-old  woman  who 
had  formerly  often  sufi'ered  ^dth  violent  pains  in  the  gastric  region  there 
gradually  developed  in  association  with  rise  in  temperature  a  resistance  in 
the  epigastrium,  fat-stools,  and  glycosuria.  After  a  transitory  improvement, 
the  manifestations  grew  worse  again,  and  a  piece  of  necrotic  pancreas  tissue 
was  removed  on  operation.  A  second  operation  Avas  necessary  on  account  of 
suppuration  of  the  gall-bladder,  after  AA-hich  the  febrile  process  ceased,  the 
fat-stools  and  the  glycosuria  disappeared;  after  some  time  there  Avas  a 
recurrence  of  the  fat-stools,  and  of  the  sugar  up  to  5  per  cent. 

Acute  hemorrhagic  pancreatitis  was  first  described  by  Balser.  Later  the 
clinical  picture  was  accurately  described  chiefly  by  Korte.  According  to 
the  recent  experimental  iuA-estigations  it  is  to  be  assumed  that  there  first 
occurs  necrosis  of  the  pancreatic  tissue  through  infection  from  the  intestine 
or  through  the  pancreatic  duct  (Korte,  Opie)  on  account  of  nutriliA-e  disturb- 
ances, and  then  this  goes  on  to  fat  necrosis  through  the  action  of  the  pancre- 
atic juice.  The  fat  necrosis  probably  traA'els  further  by  Avay  of  the  lymph 
channels,  and  then  the  pancreatic  secretion  gets  into  the  circulation  and 
acts  toxic  (Gulecke  and  :'.  Bergmann).  Disturbances  in  sugar  metaboKsm 
are  10  be  expected,  only  if  the  process  inA-oh'es  the  greater  part  of  the  gland 
and  is  not  too  fulminant. 


520  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 

It  is  very  probable  the  chronic  inflammatory  processes  of  the  pancreas 
occur  more  frequently  from  infection  through  the  pancreatic  duct  than  we 
had  previously  supposed.  HirscJifcld  described  three  cases  in  which  at  the 
end  of  an  influenza  or  of  febrile  angina  there  occurred  either  swelling  of  the 
liver  and  gastric  distress,  or  colicky  pains  and  glycosuria  of  2  to  6  per  cent. 
After  lasting  one  to  five  months  the  pains  disappeared.  Sometimes  chronic 
pancreatitis  occurs  in  cholehthiasis,  although  here  the  insular  apparatus 
is  affected  only  rarely.  Mayo  Robson  found  only  four  cases  of  diabetes 
(0.2  per  cent,  of  0.4  per  cent,  sugar)  among  sixty-five  cases  with  stones  in 
the  ductus  choledochus  and  with  hard  enlarged  pancreas.  In  three  cases 
the  sugar  vanished  after  the  operation.  Later  one  case  passed  into  severe 
diabetes. 

Before  I  enter  more  intimately  into  chronic  pancreatitis  and  pancreatic 
cirrhosis.  I  would  mention  a  special  form  of  it,  namely,  the  luetic.  The  heredi- 
tary syphilitic  form  is  apparently  chiefly  interstitial,  and  avoids  the  insular 
apparatus,  on  which  account  it  almost  always  pursues  its  course  without 
glycosuria.  The  syphilitic  pancreatitis  of  adults  is  either  gummatous 
{Hernheimer,  Hirschj'eld) ,  or  interstitial.  The  latter  form,  if  it  progresses,  may 
also  temporarily  damage  the  insular  apparatus  and  thus  lead  to  glycosuria. 
ChrcUizer,  Ehrmann,  Albu  ct  al.,  report  such  cases.  In  the  case  of  Chrelitzer,  a 
relapse  of  lues  occurred  ten  years  after  the  ]')rimary  afl'ection.  Simultaneously 
with  the  exanthema  occurred  abdominal  pains  radiating  toward  the  back, 
vomiting,  meteorism,  jaundice,  swelHng  of  the  liver  and  rise  of  temperature. 
A  hard  tumor  was  palpable  deep  between  the  navel  and  the  xiphoid  process. 
In  the  urine  was  found  2.2  per  cent,  of  sugar.  Cure  occurred  spontaneously. 
In  Ehrmann''^  case  an  extremely  severe  diabetes  (8  per  cent,  of  sugar,  acetone) 
developed  at  the  time  of  the  outbreak  of  a  syphilitic  exanthema.  The 
inunction  cure  was  interrupted  and  an  antidiabetic  regimen  introduced.  All 
symptoms  disappeared  within  eight  days.  Albus  case  was  very  chronic. 
In  a  forty-four-year  old  man  (primary  affection  fourteen  years  previous) 
there  developed  gastric  disturbances,  emaciation,  jaundice,  and  enlargement 
of  the  hver;  after  a  longer  time,  fat  stools  and  glycosuria  (0.9  per  cent.); 
also  a  tumor  was  palpable  deeply.  Under  enemas  of  potassium  iodide,  and 
pancreatin,  improvement  occurred;  and  after  several  months  tumor  and 
glycosuria  disappeared  and  the  case  was  cured.  In  general,  lues  does  not 
play  a  great  role  in  the  etiology  of  diabetes,  v.  Xoordcn  found  syphilis  in 
the  history  of  1.2  per  cent,  in  male  individuals  under  twenty  years  of  age, 
7.1  per  cent,  in  males  over  twenty,  and  2.3  per  cent,  of  female  diabetics  of 
all  ages. 

Chronic  indurative  pancreatitis  is  a  very  common  disease.  It  may  proceed 
from  the  vessels  (arteriosclerosis,  endarteritis  obliterans)  or  from  the  excre- 
tory ducts.  It  may  be  diffuse  or  circumscribed.  In  gall-stone  aft'ections 
there  may  sometimes  occur  isolated  sclerosis  of  the  head  of  the  pancreas 


GROSS    ANATOMICAL    DISTURBANCES  52 1 

(Riedel).  Chronic  indurative  pancreatitis  often  occurs  simultaneously  with 
atrophic  cirrhosis  of  the  liver,  especially  in  alcohoHcs.  Weintraud,  Bence, 
and  others  have  described  such  cases,  in  which  as  a  result  of  high-grade  de- 
ficiency of  pancreatic  function  there  occurred  pronounced  disturbances  of 
fat  absorption.  In  Bence's  case  severe  diabetes  existed.  The  section  showed 
a  marked  disappearance  of  the  pancreas  and  sclerosis;  the  islands  of  Langer- 
hans  were  entirely  destroyed,  and  only  remnants  of  the  acinous  tissue  were 
present.  In  very  severe  alcoholism  there  exists  simultaneously  sclerosis  of 
the  liver  and  pancreas  (and  suprarenals),  sometimes  associated  with  the 
deposition  of  iron-containing  pigment  in  the  liver,  pancreas,  skin,  etc.  (cir- 
rhose  bronzee  or  diabete  bronzee).  Atrophy  of  the  pancreas  with  sclerosis 
is  a  common  finding  in  diabetes  meUitus.  When  it  occurs  the  insular  appa- 
ratus is  mostly  rather  severely  damaged.  We  shall  come  back  later  to  the 
consideration  of  v.  Hansemann's  granular  atrophy  of  the  pancreas  and  the 
interacinous  sclerosis  of  Opie,  and  the  sclerosis  periacinous  of  Lipine,  and 
Lemoine  and  Laimois.  In  severe  damaging  of  the  glandular  parenchyma, 
there  may  in  such  cases  occur  disturbances  of  absorption.  In  the  case  of 
Keuthe,  that  had  previously  been  described  by  Gldssner  and  Siegel,  there 
existed  a  moderate  disturbance  of  the  fat  absorption  (the  fat  in  the  diet  was 
slight  only)  and  several  times  transitory  glycosuria  (of  0.3  per  cent,  to  0.7  per 
cent.).  The  autopsy  showed  marked  atrophy  of  the  pancreas,  the  duct  of 
Wirsung  was  not  to  be  found,  the  islands  of  Langerhans  were  in  part  retained 
or  were  hyper trophied.  Sometimes  the  marked  sclerosis  of  the  pancreas  is 
the  result  of  a  lithiasis  pancreatitis.  Lithiasis  of  the  pancreas  may  occur 
isolated;  but  not  rarely  it  is  combined  with  cholelithiasis.  In  certain  cases 
kidney  stones  were  also  found.  In  this  event,  we  may  speak  of  a  general 
stone  diathesis,  that  not  rarely  is  familial.  The  pancreas  stones  are  whitish, 
brittle,  crumbly,  unlike  gall-stones  they  contain  no  pigment,  but  on  the  con- 
trary are  rich  in  lime-salts,  so  that  under  circumstances  they  can  be  demon- 
strated by  the  X-rays.  Probably  they  usually  originate  (as  do  gall-stones) 
after  a  chronic  catarrh  has  established  in  the  duct  system  of  the  pancreas. 
Often  the  larger  and  smaller  pancreatic  passages  are  plugged  up  with  stones. 
In  other  cases  there  are  found  one  or  more  larger  stones,  which  pass  with 
severe  colic,  and  may  temporarily  or  permanently  block  up  the  larger  ducts 
of  the  pancreas,  or  even  the  principal  excretory  duct.  Behind  the  place  where 
the  stone  lodges  there  often  occurs  a  dilatation  of  the  passage  in  question  and 
an  indurative  pancreatitis,  which  at  the  beginning  affects  the  islands  but  little, 
but  no  longer  duration  damages  them  severely.  The  pancreatic  colics  that 
Minnich  first  intimately  described  commence  with  severe  girdle-like  pains 
radiating  to  the  back  and  even  to  the  shoulder.  In  a  case  that  I  saw,  the 
girdle-hke  pains  associated  with  symmetrical  hyperesthetic  zones  over 
the  ihac  crests  led  me  to  think  of  a  spinal  affection,  until  on  the  next  day  the 
occurrence  of  very  voluminous  stools  with  creatorrhea  and  steatorrhea  made 


522  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

possible  the  diagnosis  of  occlusion  of  the  duct  of  Wirsung  by  a  pancreatic 
stone.  The  impaction  of  a  pancreatic  stone  can  also  take  place  without  pains. 
This  was  the  case  in  a  patient  observed  by  Gigon  and  me.  Also  here  there 
recurred  from  one  day  to  another  all  the  acute  absorptive  disturbances 
characteristic  of  impaction  of  a  pancreatic  stone,  without,  however,  the  exist- 
ence of  colic.  At  autopsy  there  was  found  in  addition  to  numerous  small 
stones  in  the  pancreas  a  stone  the  size  of  a  cherry  stone  which  fully  occluded 
the  place  of  opening  of  the  pancreatic  duct  into  the  ampulla  of  Vater. 

The  high-grade  indurative  pancreatitis  that  so  frequently  complicates 
stone  of  the  pancreas,  especially  on  the  occlusion  of  the  chief  excretory  duct 
by  a  stone,  makes  intelhgible  the  fact  that  lithiasis  of  the  pancreas  is  so  fre- 
quently associated  with  disturbances  of  the  sugar  metabolism.  Oser  reports 
that  among  seventy  cases,  diabetes  or  at  least  temporary  glycosuria  was 
observed  in  twenty-four,  that  is,  in  more  than  34  per  cent,  of  the  cases. 
Lazarus  indeed  found  it  in  45  per  cent.  Albii  mentions  an  interesting  case. 
The  test  for  alimentary  glycosuria  had  previously  resulted  negative.  There 
existed  a  tumor  in  the  region  of  the  pancreas  which  distinctly  enlarged  during 
a  severe  attack  of  colic.  On  test  for  alimentary  glycosuria,  2.9  per  cent,  of 
sugar  was  found  in  the  urine.  In  the  case  of  mine  previously  mentioned  a 
shght  diabetes  existed  before  the  colic.  The  patient  could  easily  be  made 
sugar-free  by  a  strict  diet.  After  the  colic  and  the  occurrence  of  the  fat 
stools,  the  diabetic  metabolic  disturbances  became  essentially  worse;  after 
about  eight  days  the  voluminous  stools  disappeared ;  after  another  two  weeks 
the  stools  were  entirely  normal,  even  after  heavy  overloading  with  fat; 
simultaneously  with  this  there  was  also  observed  a  retrogression  of  the  dia- 
betic metabolic  disturbances,  so  that  the  patient  again  became  temporarily 
sugar-free.  Apparently  as  a  sequel  of  severe  inflammatory  processes  in  the 
ducts,  the  islands  of  Langerhans  do  not,  in  occlusion  of  the  duct  of  Wirsung 
by  stone,  behave  so  refractory  as  in  animal  experimentation  after  ligation 
of  the  excretory  ducts.  It  is  also  of  importance  for  the  occurrence  of  dis- 
turbances in  sugar  metabolism,  whether  the  second  pancreatic  duct  is  ob- 
literated or  is  likewise  closed  by  a  stone,  or  whether  numerous  intrapancreatic 
passages  are  rendered  impassable;  as  the  intensity  and  the  extcnsiveness  of 
the  sclerotic  processes  are  in  part  dependent  on  these  factors. 

These  circumstances  are  also  important  for  the  occurrence  of  disturbances 
of  absorption.  It  is  without  other  considerations  to  be  expected  that  these 
only  become  manifest  in  a  pronounced  manner  when  the  flow  of  pancreatic 
juice  into  the  intestine  cither  is  fully  interrupted,  or  at  least  almost  completely 
ceases.  I  would  like  to  enter  here  upon  the  question  as  to  the  relationship 
that  exists  between  the  disturbances  of  absorption  that  occur  on  cessation 
of  the  pancreatic  juice  in  man,  and  the  internal  secretion  of  the  pancreas. 
At  the  beginning,  when  the  animal  experiments  of  Abelmann  were  regarded 
as  indicative,  the   question   seems  to  have  become   entirely  cleared.     We 


GROSS   ANATOMICAL   DISTURBANCES  523 

•referred  the  occurrence  of  absorptive  disturbances  to  the  absence  of  the  pan- 
creatic juice,  the  occurrence  of  glycosuria  to  insufficiency  of  the  internal 
secretory  activity  of  the  pancreas.  In  more  recent  times  this  question  has 
encountered  confusion  in  the  literature.  Naturally  there  occur  disturbances 
of  fat  and  albumin  absorption  when  the  production  of  pancreatic  juice  is 
normal,  as  in  profuse  diarrheas  of  different  origin,  amyloidosis  of  the  intestine, 
etc.  We  know  further  the  disturbances  of  fat  absorption  in  complete  cutting 
off  of  the  bile  from  the  intestine  and  also  the  fat  stools  in  certain  forms  of 
Basedow's  disease;  as  important  differential  criteria  against  both  the  last- 
mentioned  forms  are,  since  Friedrich  v.  Miiller's  investigations  and  the 
observations  of  v.  Noorden's  clinic  as  to  Basedow's  disease,  the  disturbance 
in  fat  decomposition  that  occurs  on  the  cutting-off  of  the  pancreatic  juice 
and  again  the  slight  holdings  in  soaps.  To  this  should  be  added  the  fact 
that  in  typical  pancreatic  stools,  the  creatorrhea,  that  is  the  more  prominent 
occurrence  of  striped  muscular  fibers,  dominates  the  microscopical  picture. 
With  this  is  associated  a  more  distinct  loss  of  nitrogen  by  way  of  the  feces 
than  is  observed  in  other  disturbances  of  absorption.  Finally  there  have  been 
worked  out  a  series  of  methods  for  demonstrating  the  absence  of  a  proteolytic 
or  amylolytic  ferment  in  the  feces  obtained  after  purgation.  Many  authors 
have  raised  objections  to  these  diagnostic  postulates,  as  they  have  observed 
cases  of  disease  of  the  pancreas  in  which  the  characteristic  disturbances  of 
absorption  were  absent,  in  spite  of  complete  cutting-off  of  the  pancreatic 
juice  from  the  intestine.  Thus  Deucher,  Albu,  Ury,  Alexander,  Keuthe  and 
Brugsch  saw  normal  fat  splitting  in  pancreatic  diseases.  Also  creatorrhea 
is  sometimes  absent.  We  might  suppose  that  in  these  cases  the  other  diges- 
tive ferments  have  entirely  taken  over  the  role  of  the  pancreatic  secretion. 
Brugsch  explains  that  on  simple  occlusion  of  the  excretory  duct  of  the  pan- 
creas there  occur  no,  or  only  temporary,  absorptive  disturbances,  but  more 
intense  disturbances  only  when  the  pancreas  is  completely  degenerated, 
or  the  gland  tissue  is  for  greater  part  destroyed  through  carcinoma  or  ab- 
scesses, etc.  Then  only  would  loss  of  fat  occur  up  to  60  per  cent,  and  the 
nitrogen  loss  up  to  20  per  cent.  This  hypothesis,  which  has  indeed  not  been 
based  on  the  examination  of  a  definite  case,  but  has  been  influenced  by  the 
views  of  Lonihroso  which  we  have  already  criticised,  is  not  decisive.  I  refer 
only  to  the  previously  mentioned  case  of  Gigoii,  in  which  the  absorptive 
disturbances  set  in  suddenly  on  occlusion  by  stone  and  lasted  until  death. 
The  pancreas  cannot  degenerate  in  a  day;  if,  however,  it  has  already  been 
markedly  degenerated,  we  cannot  readily  see  how  it  can  have  furnished 
sufficient  secretion  up  to  the  day  on  which  the  occlusion  occurred.  Too,  it 
seems  especially  inappropriate  to  apply  off-hand  to  human  pathology  the  re- 
sults of  animal  experiments,  which  as  we  have  seen  are  not  as  yet  fully  ex- 
plained. It  would  indeed  be  conceivable  that  the  other  digestive  secretions 
in  the  dogs  render  the  pancreatic  secretion  less  indispensable  than  in  man. 


524  DISEASES    OF    THE    IXSULAR    APAPARTUS    OF    THE    PANXREAS 

In  human  pathology,  the  conditions  seem  to  me  to  be  clearer  and  to  justify 
a  single  standpoint,  v.  Noorden  and  Salomon  have  pointed  out  in  this  re- 
gard that  in  cases  of  absence  or  insufficiency  of  the  pancreatic  juice,  the  ab- 
sorptive disturbances  become  manifest,  if  the  intestine  is  overloaded  with 
fat;  if  in  this  functional  test,  butter  stools  occur  we  may  take  it  for  granted 
that  there  is  certainly  a  disease  of  the  pancreas  or  absence  of  the  pancreatic 
juice.  Also  this  is  true  if  creatorrhea  makes  its  appearance.  It  should 
not  be  forgotten  that  in  many  of  the  cases  of  pancreatic  disease  in  the  litera- 
ture (especially  in  carcinoma,  in  which  fat  stools  are  absent,  on  account  of 
the  increasing  cachexia),  the  intake  of  diet  was  very  slight  at  the  time  of  the 
observation.  We  must  here  again  refer  to  the  anatomical  relations  of  the 
duct  system.  We  must  consider  that  if  the  second  duct  of  the  pancreas  is 
not  obliterated  or  occluded,  enough  pancreatic  juice  may  still  reach  the  in- 
testine, even  if  the  principal  duct  be  completely  occluded,  that  the  disturb- 
ance does  not  become  manifest  even  on  heavy  overloading.  As  far  as  the 
fat  splitting  is  concerned,  Salomon  has  pointed  out  that  during  the  tedious 
procedure  of  drying  the  stools  on  the  water-bath,  always  more  fatty  acids 
occur.  If  we  do  not  take  this  into  account,  we  may  arrive  at  entirely  false 
values  for  fat  splitting.  We  may  summarize  by  saying  that  markedly 
lessened  or  absent  production  of  pancreatic  juice,  or  cutting-ofT  of  the 
pancreatic  juice  from  the  intestine,  leads  in  man  to  characteristic  absorptive 
disturbances. 

I  have  entered  into  detail  into  these  conditions,  because  we  require  a 
clear  formularization  if  we  wish  to  enter  into  the  question  as  to  how  far  the 
internal  secretory  activity  of  the  pancreas  is  independent  of  the  external 
secretory  activity,  and  whether  these  disturbances  occur  isolated  in  the 
gross  anatomical  diseases  of  the  pancreas.  In  the  acutely  onsetting,  severe, 
damagings  of  the  organ  (suppurative  or  acute  hemorrhagic  pancreatitis, 
necrosis  of  the  pancreas  or  apoplexy  of  the  pancreas)  it  is  intelligible  that  we 
do  not  see  much  of  the  disturbance  of  the  external  or  internal  secretory 
activity  of  the  pancreas.  Often,  too,  in  complete  extirpation  of  the  pancreas 
in  animal  experimentation,  the  sugar  does  not  occur  immediately  if  septic 
processes  are  present  at  the  same  time.  When  diet  is  low  or  not  ingested 
at  all,  of  course  the  absorptive  disturbances  do  not  occur  either.  If  the  course 
is  subacute,  as  a  rule  both  disturbances  are  present.  In  tumors  of  the  pan- 
creas, the  behavior  of  the  disturbances  varies  very  much.  Cysts  may  leave 
behind  sufficient  functionating  pancreatic  parenchyma  and  hence  may  pursue 
their  course  without  any  disturbance  whatsoever.  If  the  greater  ])art 
of  the  pancreas  takes  part  in  the  process  sympathetically,  a  latent  in- 
sufficiency of  both  functions  may  develop  that  may  eventually  become 
evident  only  on  overloading;  although  it  is  intelligible  that  in  individual  cases 
on  account  of  especial  anatomical  relation  the  absorptive  disturbances  may 
become  more  distinct  through  compression  of  the  duct  system.     In  carcinoma 


GROSS    ANATOMICAL    DISTURBANCES  525 

of  the  pancreas  it  seems  that  the  islands  of  Langerhans  hold  out  longer  against 
the  carcinomatous  infiltration  than  do  the  acini.  As  the  carcinoma  usually 
is  seated  in  the  head  of  the  pancreas  it  not  infrequently  happens  that  there 
is  complete  shutting  off  of  secretion  through  compression  of  the  chief  duct, 
and  hence  a  distinct  prominence  of  absorptive  disturbances.  We  should 
consider,  of  course,  that  the  ingestion  of  food  in  such  a  case  is  very  slight  on 
account  of  the  cachexia. 

In  carcinoma  we  not  rarely  observe,  in  addition  to  this  that  the  intensity 
of  the  glycosuria  diminishes  with  increase  in  the  cachexia,  or  the  sugar  en- 
tirely disappears.  This  is  entirely  comprehensible.  We  see  even  in  the 
pancreasless  dog  the  glycosuria  diminish,  if  with  the  weakening  of  the  liver 
processes  the  mobilization  of  sugar  is  also  less.  In  slight  grades  of  chronic 
indurative  or  more  atrophic  pancreatitis  no  disturbances  in  carbohydrate 
metabolism  need  necessarily  be  present.  In  advanced  cases  it  may  very  well 
be  assumed  that  the  function  of  the  insular  apparatus  has  often  suffered 
previous  damage  and  has  thus  led  to  disturbances  in  the  sugar  metabolism. 
We  shall  see  later  that  this  form  of  pancreatitis  not  rarely  forms  the  patho- 
logico-anatomical  stratum  for  the  "genuine"  diabetes  mellitus.  In  this, 
as  is  well  known,  no  absorptive  disturbances  occur,  although  the  antidia- 
betic diet  mostly  means  a  considerable  and  permanent  overloading  of  the 
fat  absorption.  In  former  times  this  was  associated  with  a  heavy  overload- 
ing of  the  intestines  with  meat.  Thus  can  the  production  of  pancreatic  juice 
be  strongly  limited  without  disturbances  of  absorption  becoming  manifest. 
These  occur  only  with  the  higher  grades  of  atrophy  of  the  pancreas.  The 
most  important  are  the  cases  with  occlusion  by  stone,  and  those  of  consecutive 
sclerosis.  In  stoppage  of  the  duct  by  stone  we  have  in  addition  the  suddenly 
appearing  characteristic  absorptive  disturbances,  which  are  fully  developed, 
and  most  often  the  latent  or  manifest  disturbances  in  carbohydrate  me- 
tabolism that  had  already  been  present,  perhaps  because  the  catarrh  of  the 
duct  system  has  for  a  long  time  led  to  incrustation  of  the  ducts  and  to  in- 
durative pancreatitis.  There  are,  however,  cases  in  which,  at  least  at  the 
beginning,  there  exist  fully  developed  disturbances  of  absorption,  but  only 
minimal  latent  disturbances  of  carbohydrate  metabolism.  These  cases  are 
entirely  intelligible,  if  through  impaction  of  a  gall-stone  or  through  other 
factors  leaving  the  pancreas  for  greater  part  intact,  the  supply  of  pancreatic 
juice  is  interrupted.  Ehrmann  and  others,  have  described  such  cases.  As 
example  I  submit  the  following: 

Observation  LXVIII. — R.  M.,  thirty-five  years.  Entrance  into  the  dinic  Nov.,  191 1. 
Until  one  and  one-half  years  ago  the  patient  was  entirely  well.  Then  obstipation  that 
often  lasted  four  or  five  days  set  in,  and  also  slight  headache.  For  about  seven  months 
severe  colicky  pains  in  the  right  hypochondrium,  about  ten  days  after  this  jaundice,  that 
has  lasted  until  to-day.  Since  this  time  four  or  five  bowel  movements  daily  that  were 
very  voluminous,  "  more  than  he  ingested  as  food."     The  stools  are  clay-colored.     In  spite 


526  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

of  this  fact  the  appetite  remained  very  good,  the  patient  fell  off  rapidly.  The  patient  is 
almost  entirely  impotent.  ]\Iore  severe  jaundice,  hair  on  head  very  much  thinned  out, 
that  in  the  axillae  almost  entirely  absent,  sparse  on  the  pubis.  Colossal  hydrops  of  the 
gall-bladder.  In  addition,  in  the  middle  line,  very  deep,  is  a  resistance  hard  to  outline. 
Ascites. 

Rontgen  examination:  diffuse  aortic  extension  of  a  moderate  degree.  Wassermann 
negative.  Increased  peristalsis  of  the  stomach,  although  emptying  of  the  stomach  is  not 
essentially  slowed.  Urine  deeply  jaundiced,  no  sugar.  Chemical  examination  of  the 
stomach  contents  normal. 

The  stools  (3-4  daily)  are  very  massive  and  are  acholic;  urobilin  test  constantly  nega- 
tive; minimal,  quantitatively  not  estimable  amounts  of  urobilogen  {Dr.  Charnas).  The 
stools  are  of  gray-white  color,  glittering  with  fat,  of  very  foul  odor,  microscopically  show 
much  neutral  fat,  soap  and  fatty  acid  needles  and  striated  muscle  fibers.  By  loading  with 
fat  (250  gm.  oats,  oatmeal,  and  300  gm.  butter)  there  occur  typical  butter  stools.  The 
test  was  repeated  five  times  always  with  positive  results. 

The  chemical  examination  of  the  stools  (with  the  overloading  test)  showed  38.5  per 
cent,  unsplit  fat  and  64.2  per  cent,  fat  in  the  form  of  fat  acids  and  soaps.  The  chemical 
examination  of  the  butter-stools  showed  71.7  per  cent,  neutral  fat. 

The  examination  of  the  stool  for  tryptic  ferment  according  to  Gross,  and  also  for  dia- 
static  ferment  according  to  Wolgcmiit  showed  only  traces.  In  one  examination,  however, 
there  was  found  slight,  but  distinct  tryptic  and  diastatic  action. 

Five  tests  for  alimentary  glycosuria  (100  gm.  of  dextrose,  fasting)  were  always  negative. 

During  the  stay  at  the  hospital  there  often  occurred  colicky  pains  in  the  gall- 
bladder region. 

The  ascitic  fluid  had  a  specific  gravity  of  1012,  8  per  cent,  albumin.  The  albumin 
bodies  precipitated  by  acetic  acid  were  present  only  in  traces. 

The  Salomon-SaxVs  carcinoma  reaction  was  positive. 

Although  the  Salomon-SaxVs  test  as  well  as  the  ascites  spoke  for  a  new  growth,  yet  the 
possibility  of  an  occlusion  of  the  ductus  choledochus  by  stone  could  not  be  excluded;  so  that 
the  patient  was  operated  on.  There  was  found  at  operation,  deep  down  in  the  abdominal 
cavity,  a  tumor  whose  situation  was  not  quite  clear.  Cholecystogastrostomy  was  done. 
Death  occurred  some  weeks  afterward.  Section  showed  a  scirrhous  carcinoma  of  the 
head  of  the  pancreas,  with  closure  of  the  pancreatic  duct,  marked  dilatation  of  the  passages 
in  the  body  and  tail  of  the  pancreas.  The  ducts  were  filled  with  a  milky  yellowish  fluid. 
The  ductus  choledochus  was  occluded  about  1J2  crn-  above  the  papilla  of  Vater,  and 
there  was  marked  dilatation  of  the  bile  ducts  above  it. 

The  case  described  fulfills  all  the  conditions  that  we  could  establish 
at  a  physiological  experiment.  There  arc  present  all  symptoms  that  are 
characteristic  for  the  cutiing-off  of  the  pancreatic  juice  {and  the  bile),  icJiile 
the  carbohydrate  metabolism  icas  entirely  normal  even  on  heavy  overloading. 
Such  cases  have  an  important  significance.  They  show  us  that  in  human 
beings  the  internal  secretory  and  the  external  secretory  activity  of  the  pancreas 
are  fully  independent  of  each  other  within  wide  limits. 

B.  Genuine  Diabetes  Mellitus 

It  is  not  my  intention  here  to  depict  the  symptomatology  of  diabetes 
mellitus  in  exhaustive  fashion.  Much  more  will  I  limit  myself  merely  to 
sketching  the  clinical  picture,  assigning  only  somewhat  more  space  to  the 


GENUINE    DIABETES    MELLITUS  527 

metabolic  disturbances  in  order  to  discuss  later  the  position  of  the  pancreas 
in  the  pathogenesis  of  diabetes  mellitus. 

The  Carbohydrate  Metabolism.— Among  the  symptoms  of  diabetes 
mellitus,  glycosuria  is  the  most  striking  for  physician  and  laity.  Theoretically 
and  also  more  practically  important,  certainly,  is  hyperglycemia,  for  glycosuria 
is  only  a  result  of  this.  There  is  in  diabetes  mellitus  an  excretion  of  sugar 
without  hyperglycemia,  but  not  rarely  does  there  occur  hyperglycemia 
without  excretion  of  sugar.  If  the  diabetes  has  existed  for  a  long  time,  the 
kidneys  lose  their  finer  sensitiveness  for  the  heightening  of  the  blood-sugar 
contents,  they  gain  in  sugar-imperviousness  (v.  Noorden,Liefmann,  and  Stern). 
There  is  also  in  such  cases  no  proportion  between  the  degree  of  the  hypergly- 
cemia and  the  intensity  of  the  glycosuria.  Especially  is  this  true  for  the  dia- 
betes of  old  age.  The  fact  is  also  very  important,  as  may  be  expected,  that 
the  tolerance  only  rises  when  the  sugar  in  the  blood  has  been  for  a  long  time 
normal,  and  that  a  series  of  symptoms,  that  we  regard  as  the  sequel  of  a  long- 
continuing  hyperglycemia  (furunculosis,  impotence,  diabetic  gangrene, 
rheumatoid  pains,  etc.)  only  vanish  when  the  hyperglycemia  is  combated. 

For  the  assumption  of  diabetic  disturbance  of  metabolism  there  is  neces- 
sary the  demonstration  that  the  sugar  excreted  in  the  urine  is  grape-sugar. 
Further,  there  must  be  excluded  a  series  of  conditions  that  according  to 
experience  are  associated  with  a  temporary  excretion  of  sugar,  or  at  least 
appreciably  reduce  the  tolerance  for  carbohydrates.  Of  such  conditions  I 
mention  acute  febrile  diseases,  intoxication  with  carbon  monoxide  or  mor- 
phine, and  asphyxic  conditions,  etc. 

It  should  further  be  considered  that  after  copious  ingestion  of  sugar, 
sometimes  slight  amounts  of  sugar  are  found  in  the  urine  of  even  normal 
human  beings.  The  glycosurias  in  certain  ductless  diseases  especially  in 
Basedow's  disease  and  in  acromegaly  are  considered  in  detail  in  the  chapters 
on  the  subject.  We  shall  consider  later  the  matter  of  nervous  glycosurias 
(in  traumatic  neurosis,  hysteria,  neurasthenia,  and  in  certain  nervous  diseases, 
such  as  tabes  and  [general]  paralysis). 

I  might  here  mention  the  laws  that  the  excretion  of  sugar  follows.  In  the 
great  majority  of  cases  of  diabetes  we  can  observe  a  narrow  relation  between 
intake  of  food  and  excretion  of  sugar.  If  we  place  such  a  diabetic  on  a  diet 
of  a  constant  composition,  the  excretion  of  sugar  sets  in  at  a  definite  level  and 
maintains  it  for  a  long  time.  In  cases  that  have  not  advanced  entirely  too  far, 
it  is  known  that  the  tolerance  may  be  influenced  by  a  corresponding  dietetic 
regime.  If  the  patient  on  account  of  the  Hmitation  of  the  sugar-forming 
material  becomes  sugar-free,  and  if  the  amount  of  sugar  in  the  blood  remains 
for  a  long  time  normal,  a  reparation  occurs,  so  that  later  a  diet  without  gly- 
cosuria may  be  borne  that  formerly  led  to  sugar-excretion.  On  the  other 
hand  the  tolerance  is  depressed  when  a  high  sugar-content  of  the  blood  has 
existed  for  a  Ions  time. 


526  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

of  this  fact  the  appetite  remained  very  good,  the  patient  fell  off  rapidly.  The  patient  is 
almost  entirely  impotent.  ]\Iore  severe  jaundice,  hair  on  head  very  much  thinned  out, 
that  in  the  axillae  almost  entirely  absent,  sparse  on  the  pubis.  Colossal  hydrops  of  the 
gall-bladder.  In  addition,  in  the  middle  line,  very  deep,  is  a  resistance  hard  to  outline. 
Ascites. 

Rontgen  examination:  diffuse  aortic  extension  of  a  moderate  degree.  Wassermann 
negative.  Increased  peristalsis  of  the  stomach,  although  emptying  of  the  stomach  is  not 
essentially  slowed.  Urine  deepl}^  jaundiced,  no  sugar.  Chemical  examination  of  the 
stomach  contents  normal. 

The  stools  (3-4  daily)  are  very  massive  and  are  acholic;  urobilin  test  constantly  nega- 
tive; minimal,  quantitatively  not  estimable  amounts  of  urobilogen  {Dr.  Charnas).  The 
stools  are  of  gray- white  color,  glittering  with  fat,  of  very  foul  odor,  microscopically  show 
much  neutral  fat,  soap  and  fatty  acid  needles  and  striated  muscle  fibers.  By  loading  with 
fat  (250  gm.  oats,  oatmeal,  and  300  gm.  butter)  there  occur  typical  butter  stools.  The 
test  was  repeated  five  times  always  with  positive  results. 

The  chemical  examination  of  the  stools  (with  the  overloading  test)  showed  38.5  per 
cent,  unsplit  fat  and  64.2  per  cent,  fat  in  the  form  of  fat  acids  and  soaps.  The  chemical 
examination  of  the  butter-stools  showed  71.7  per  cent,  neutral  fat. 

The  examination  of  the  stool  for  tryptic  ferment  according  to  Gross,  and  also  for  dia- 
static  ferment  according  to  Wolgemiit  showed  only  traces.  In  one  examination,  however, 
there  was  found  slight,  but  distinct  tryptic  and  diastatic  action. 

Five  tests  for  alimentary  glycosuria  (100  gm.  of  dextrose,  fasting)  were  always  negative. 

During  the  stay  at  the  hospital  there  often  occurred  colicky  pains  in  the  gall- 
bladder region. 

The  ascitic  fluid  had  a  specific  gravity  of  1012,  8  per  cent,  albumin.  The  albumin 
bodies  precipitated  by  acetic  acid  were  present  only  in  traces. 

The  Salomon-SaxVs  carcinoma  reaction  was  positive. 

.\lthough  the  Salomon-SaxVs  test  as  well  as  the  ascites  spoke  for  a  new  growth,  yet  the 
possibility  of  an  occlusion  of  the  ductus  choledochus  by  stone  could  not  be  excluded;  .so  that 
the  patient  was  operated  on.  There  was  found  at  operation,  deep  down  in  the  abdominal 
cavity,  a  tumor  whose  situation  was  not  quite  clear.  Cholecystogastrostomy  was  done. 
Death  occurred  some  weeks  afterward.  Section  showed  a  scirrhous  carcinoma  of  the 
head  of  the  pancreas,  with  closure  of  the  pancreatic  duct,  marked  dilatation  of  the  passages 
in  the  body  and  tail  of  the  pancreas.  The  ducts  were  filled  with  a  milky  yellowish  fluid. 
The  ductus  choledochus  was  occluded  about  i^i  cm.  above  the  papilla  of  ^'ater,  and 
there  was  marked  dilatation  of  the  bile  ducts  above  it. 

The  case  described  fulfills  all  the  conditions  that  we  could  establish 
at  a  physiological  experiment.  There  arc  present  all  symptoms  that  are 
characteristic  for  the  cutting-ojff  of  the  pancreatic  juice  {and  the  bile),  while 
the  carbohydrate  metabolism  was  entirely  normal  even  on  heavy  overloading. 
Such  cases  have  an  important  significance.  They  show  us  that  in  human 
beings  the  internal  secretory  and  the  external  secretory  activity  of  the  pancreas 
are  fully  independent  of  each  other  within  wide  limits. 

B.  Genuine  Diabetes  Mellitus 

It  is  not  my  intention  here  to  depict  the  symptomatology  of  diabetes 
mellitus  in  exhaustive  fashion.  ^luch  more  will  I  limit  myself  merely  to 
sketching  the  chnical  picture,  assigning  only  somewhat  more  space  to  the 


GENUINE    DIABETES    MELLITUS  527 

metabolic  disturbances  in  order  to  discuss  later  the  position  of  the  pancreas 
in  the  pathogenesis  of  diabetes  mellitus. 

The  Carbohydrate  MetaboHsm.— Among  the  symptoms  of  diabetes 
mellitus,  glycosuria  is  the  most  striking  for  physician  and  laity.  Theoretically 
and  also  more  practically  important,  certainly,  is  hyperglycemia,  for  glycosuria 
is  only  a  result  of  this.  There  is  in  diabetes  mellitus  an  excretion  of  sugar 
without  hyperglycemia,  but  not  rarely  does  there  occur  hyperglycemia 
without  excretion  of  sugar.  If  the  diabetes  has  existed  for  a  long  time,  the 
kidneys  lose  their  finer  sensitiveness  for  the  heightening  of  the  blood-sugar 
contents,  they  gain  in  sugar-imperviousness  (v.  N  o  or  den.  Lief m  ami,  and  Stern). 
There  is  also  in  such  cases  no  proportion  between  the  degree  of  the  hypergly- 
cemia and  the  intensity  of  the  glycosuria.  Especially  is  this  true  for  the  dia- 
betes of  old  age.  The  fact  is  also  very  important,  as  may  be  expected,  that 
the  tolerance  only  rises  when  the  sugar  in  the  blood  has  been  for  a  long  time 
normal,  and  that  a  series  of  symptoms,  that  we  regard  as  the  sequel  of  a  long- 
continuing  hyperglycemia  (furunculosis,  impotence,  diabetic  gangrene, 
rheumatoid  pains,  etc.)  only  vanish  when  the  hyperglycemia  is  combated. 

For  the  assumption  of  diabetic  disturbance  of  metabolism  there  is  neces- 
sary the  demonstration  that  the  sugar  excreted  in  the  urine  is  grape-sugar. 
Further,  there  must  be  excluded  a  series  of  conditions  that  according  to 
experience  are  associated  with  a  temporary  excretion  of  sugar,  or  at  least 
appreciably  reduce  the  tolerance  for  carbohydrates.  Of  such  conditions  I 
mention  acute  febrile  diseases,  intoxication  with  carbon  monoxide  or  mor- 
phine, and  asphyxic  conditions,  etc. 

It  should  further  be  considered  that  after  copious  ingestion  of  sugar, 
sometimes  slight  amounts  of  sugar  are  found  in  the  urine  of  even  normal 
human  beings.  The  glycosurias  in  certain  ductless  diseases  especially  in 
Basedow's  disease  and  in  acromegaly  are  considered  in  detail  in  the  chapters 
on  the  subject.  We  shall  consider  later  the  matter  of  nervous  glycosurias 
(in  traumatic  neurosis,  hysteria,  neurasthenia,  and  in  certain  nervous  diseases, 
such  as  tabes  and  [general]  paralysis). 

I  might  here  mention  the  laws  that  the  excretion  of  sugar  follows.  In  the 
great  majority  of  cases  of  diabetes  we  can  observe  a  narrow  relation  between 
intake  of  food  and  excretion  of  sugar.  If  we  place  such  a  diabetic  on  a  diet 
of  a  constant  composition,  the  excretion  of  sugar  sets  in  at  a  definite  level  and 
maintains  it  for  a  long  time.  In  cases  that  have  not  advanced  entirely  too  far, 
it  is  known  that  the  tolerance  may  be  influenced  by  a  corresponding  dietetic 
regime.  If  the  patient  on  account  of  the  limitation  of  the  sugar-forming 
material  becomes  sugar-free,  and  if  the  amount  of  sugar  in  the  blood  remains 
for  a  long  time  normal,  a  reparation  occurs,  so  that  later  a  diet  without  gly- 
cosuria may  be  borne  that  formerly  led  to  sugar-excretion.  On  the  other 
hand  the  tolerance  is  depressed  when  a  high  sugar-content  of  the  blood  has 
existed  for  a  long  time. 


528  DISEASES    OF    THE    IXSULAR    APPAR,A.TUS    OF    THE    PANCREAS 

It  is  known  that  the  individual  food-stuffs  are  not  equivalent  in  their 
action  on  the  glycosuria.  Carbohydrates  and  protein  act  more  positively 
on  the  glycosuria  than  fat,  while  alcohol,  for  instance,  does  not  influence  the 
glycosuria.  Also  the  individual  carbohydrate  and  albuminous  bodies  show- 
differences  in  their  action.  Of  the  kinds  of  sugar,  maltose,  for  example,  acts 
more  glycosuric  than  glucose,  and  this  again  acts  more  strongly  than  levulose. 
However,  the  individual  diabetics  do  not  behave  the  same  throughout.  For 
example,  milk-sugar  is  borne  very  well  by  many,  others  react  to  it  with  a 
severe  excretion  of  sugar. 

Also  the  individual  protein  bodies  influence  the  glycosuria  in  different 
manners.  To  mention  only  a  few  examples,  casein  and  meat-albumin  act 
more  on  the  glycosuria  than  plant-albumin  and  egg-albumin,  the  latter  acts 
less  glycosuric  when  it  is  ingested  in  its  native  condition.  The  founda- 
tion for  this  lies  partly  in  the  fact  that  the  individual  albuminous  bodies  are 
drawn  into  decomposition  at  dift'erent  rates.  In  very  severe  cases  of  diabetes 
the  differences  vanish,  however.  Otherwise  the  individual  diabetics  act 
differently  with  regard  to  the  administration  of  protein.  Especially  severe 
cases  often  react  to  increase  of  the  ingestion  of  protein  with  a  sugar  eHmina- 
tion  relatively  stronger  than  on  the  administration  of  carbohydrates — ''pro- 
tein sensitive  cases." 

The  question  whether  in  human  diabetes  sugar  can  be  built  out  of  pro- 
tein has  been  energetically  discussed.  On  the  clinical  side  it  has  been  shown 
that  severe  cases  of  diabetes  melHtus  that  have  been  kept  for  months  on 
exclusively  meat-fat-diets,  constantly  excrete  so  much  sugar  that  it  is  hardly 
possible  to  refer  this  to  the  slight  carbohydrate-content  of  the  diet  and  to  the 
original  glycogen-content  of  the  organism.  It  is  further  known  that  in 
especially  severe  diabetics  the  excretion  of  sugar  varies  simultaneously  with 
the  ingestion  of  protein.  The  question  of  sugar-formation  out  of  protein 
can  to-day  be  answered  with  a  ''yes."  On  the  contrary  the  question  as  to 
what  extent  the  normal  or  the  diabetic  organism  can  build  sugar  out  of  pro- 
tein cannot  be  safely  decided  with  the  methods  of  investigations  of  me- 
tabolism to-day  at  our  disposal.  We  cannot  in  this  manner  make  sure  as  to  the 
origin,  as  far  as  ingested  food  material  is  concerned,  of  the  sugar  eliminated 
in  the  urine.  It  is  very  probable  that  the  sugar  also  appearing  in  the  urine 
in  slight  cases  does  not  only  depend  on  the  change  in  carbohydrates,  but  also 
on  that  of  the  protein.  Theoretical  considerations  that  I  shall  not  enter  into 
here,  speak  for  the  fact  that  from  100  gm.  of  protein  (about  16  per  cent, 
nitrogen)  not  more  than  80  gm.  of  sugar  can  be  formed.  From  i  gm.  of  X. 
therefore  would  come  about  5  gm.  sugar. 

The  question  is  much  more  complicated  by  the  fact  that  we  have,  too,  to 
regard  fat  as  a  sugar-former.  At  all  events,  however,  the  administration  of 
fat  does  not  ordinarily  increase  the  excretion  of  sugar.  On  these  facts  the 
dietetic  treatment  of  diabetes  is  for  most  part  built.     This  is  readily  under- 


GENUINE    DIABETES    MELLITUS  529 

stood  when  we  consider,  that,  as  v.  Noorden  emphasizes,  that  fat  is  transmitted 
to  the  blood  and  the  tissues  especially  by  the  lymphatic  paths,  and  from  there 
is  transported  to  the  liver  only  in  accordance  with  needs,  while  carbohydrates 
and  protein  directly  flow  to  the  Hver  through  the  portal  vein  and  increase 
the  condition  of  irritability  of  the  liver.  The  facts  that,  apart  from  theoret- 
ical considerations,  speak  for  the  formation  of  sugar  from  fat:  In  severe  cases 
of  diabetes  mellitus  we  sometimes  observe  a  not  inappreciable  increase  of 
sugar  elimination  when  we  administer  large  quantities  of  fat  during  a  hunger 
period.  In  such  cases  the  dextrose  to  nitrogen  quotient  sometimes  raises  to 
10.  Further  cases  are  known  in  which  on  abundant  ingestion  of  fat  the  dex- 
trose to  nitrogen  quotient  is  found  higher  than  in  the  period  of  less  fat  in- 
gestion. Finally,  we  have  the  results  of  exact  metabolism  investigations  in 
cases  of  very  severe  diabetes,  which  show  that  for  long  protracted  periods 
so  great  quantities  of  sugar  eliminated  that  these  cannot  be  explained  by 
the  changes  in  protein  and  carbohydrates,  v.  Noorden  has  therefore  men- 
tioned that  the  conclusions  drawn  from  the  dextrose  to  nitrogen  quotient  as 
to  the  extent  of  the  formation  of  sugar  out  of  protein  in  human  diabetes,  are 
faulty,  as  we  do  not  know  the  source  of  the  sugar. 

In  one  group  of  diabetics  this  regularity,  as  just  described,  between  the 
sugar-value  of  the  food  and  sugar  eliminations  exists  in  much  less  well  ex- 
pressed manner;  indeed  it  may  even  happen  that  this  law  may  be  broken 
down  by  other  factors.  I  shall  describe  in  detail  later  the  nervous  glycosurias 
dependent  on  organic  foundations.  I  shall  cite  here  only  the  psychical  fac- 
tor. Any  psychical  agitation,  a  fright,  a  great  excitation  on  account  of  a 
case  of  death  in  the  family,  or  business  cares,  can  suddenly  lead  to  an  out- 
break of  the  diabetes.  The  glycosuria  may  attain  a  high  grade; lassitude, 
great  thirst,  polyuria,  induce  the  patient  to  consult  the  physician,  who  then 
finds  sugar. 

Often  a  slight  limitation  of  the  diet  suffices  to  bring  about  a  disappearance 
of  the  sugar,  or  the  sugar  disappears  spontaneously.  In  a  short  time,  normal 
tolerance  is  reestablished.  At  all  events  such  cases  as  just  mentioned  are 
exceptional.  Ordinarily,  also  in  this  group  of  cases  is  the  alimentary  factor 
plainly  to  be  recognized;  but  this  is  small  in  comparison  with  the  psychical 
factors.  In  such  cases  we  see  not  rarely  that  painful  affections  of  any  sort 
at  all  may  serve  to  increase  the  excretion  of  sugar.  I  naturally  will  not  say, 
concerning  the  category  of  cases  in  which  the  alimentary  factor  dominated 
the  scene,  that  also  psychical  excitements  may  not  temporarily  lower  the 
tolerance.     In  the  nervous  cases,  however,  the  nervous  factor  predominates. 

The  Protein  Metabolism. — The  question  of  protein  need  in  diabetes  has 
been  studied  in  numerous  metabolism  investigations.  In  light  and  mod- 
erately severe  diabetics  the  protein  need  is  certainly  not  increased;  and  even 
in  severe  diabetics,  as  long  as  they  are  nourished  rationally,  we  cannot  speak 
of  an  increased  need  for  protein.     This  has  long  been  shown  by  the  protracted 

34 


530  DISEASES    OF    THE    INSULAR    APPAR.A.TUS    OF    THE    PANCREAS 

investigations  of  Wcintraud.  In  a  series  of  severe  cases,  I  have  investigated 
the  nitrogen  ehmination  of  the  ''hunger"  day  and  found  values  that  do  not 
differ  from  those  furnished  by  normal  individuals  under  like  conditions.  The 
severe  diabetic,  he  who  rationally  fed,  remains  constantly  on  a  diet  rather 
poor  in  protein,  can  indeed  enter  upon  a  striking  low  protein  need,  and  shows, 
when  abundant  protein  is  now  administered,  a  striking  tendency  to  reten- 
tion of  nitrogen.  Only  in  the  severest  cases,  before  the  fatal  coma,  does  the 
melting  down  of  protein  seem  to  raise  to  a  high  degree. 

Benedict  and  Joslin  calculate  the  nitrogen  elimination  per  kilogram  of 
body  weight  in  their  fasting-experiments,  and  find  that  the  average  of  all  in 
these  experiments  is  higher  than  in  normal  individuals;  yet  much  might  be 
said  in  objection  to  the  calculation  per  kilogram  of  body  weight,  as  the  rela- 
tion between  protoplasm  and  body-mass  becomes  disarranged  in  severe  dia- 
betics on  account  of  the  extreme  poverty  in  fat. 

In  the  severest  cases  also  the  high  elimination  of  endogenous  uric  acid 
indicates  a  marked  melting-down  of  muscle  albumin  [v.  Xoorden). 

The  qualitative  alterations  of  the  protein  metabolism  are,  apart  from  the 
high  ammonia  values  dependent  on  the  becoming  acid,  not  appreciable. 

We  shall  here  say  only  a  few  words  about  the  ketonuria  of  diabetics.  The 
ketone  bodies  originate  ^from  the  change  in  protein  and  fat  substance  on 
diminished  carbohydrate  combustion.  The  cause  of  this  origination  should 
not  be  otherwise  than  in  a  normal  man  when  he  has  been  fasting  or  has  eaten 
meat  and  fat  exclusively.  Also  in  this  case  they  are  due  to  the  lack  of 
assimilation  of  carbohydrates.  That  in  the  diabetic  such  considerably 
high  degrees  are  attained  is  comprehensible  because  in  him  is  absent  also  the 
sugar  originating  from  the  protein,  and  because  they  develop  so  very  gradu- 
all}'.  If  the  ketonuria  lasts  longer  and  attains  higher  grades,  it  gives  rise  to 
hpoidemia  and  to  fattening  of  the  liver.  In  the  most  severe  grades  of  lip- 
oidemia  the  blood  may  assume  a  light  rose-red  color  and  on  standing  may 
express  a  cream-like  dense  layer  to  the  surface. 

The  alterations  in  the  salt  metabolism  to  be  observed  in  diabetics  are 
associated  in  part  with  the  formation  or  the  elimination  of  ketone  bodies. 
Through  the  formation  of  large  amounts  of  the  ketone  acids,  alkalies  are 
withdrawn  from  the  body,  and  as  is  known,  later  the  alkalescence  of  the 
blood  sinks  and  then  the  calcium  equilibrium  is  minus  {Gcrhardt  and  W. 
Schlesinger) . 

The  equilibrium  of  water  in  diabetics  often  shows  significant  variations 
on  alterations  of  the  diet.  If  diabetics  who  formerly  had  fed  without' 
purpose  are  placed  on  a  diet  poor  in  carbohydrates  and  protein,  they  often 
gain  in  weight  in  a  short  time.  It  is  very  probable  that  this  depends  not  so 
much  on  the  filling  up  of  the  fat  deposits  and  partly  also  of  the  glycogen 
deposits,  but  much  more  on  the  retention  of  water.  In  more  fully  advanced 
cases  the  water-contents  of  the  tissues  is  much  reduced.     RiimpJ  found  the 


GENUINE    DL\BETES    MELLITUS  53 1 

water-contents  of  the  tissues  of  diabetics  who  had  died  in  coma  8}'2~t-^ 
per  cent,  lower  than  in  normal  individuals. 

The  Respiratory  Metabolism.- — The  first  experiments  as  to  the  caloric 
exchange  in  diabetics  are  those  of  Pettenkojer  and  Voit.  At  the  beginning, 
these  investigators  misinterpreted  their  experiments.  They  overlooked  on 
the  one  hand  the  loss  in  oxygen  that  the  diabetic  suffers  through  the  elimina- 
tion of  sugar  rich  in  oxygen,  and  on  the  other  hand  they  committed  the  error 
of  comparing  the  change  in  an  emaciated  diabetic  weighing  54  kilograms 
with  a  healthy  individual  weighing  71  kilograms.  These  objections  have  been 
set  forth  especially  by  Leo\  Pettenkojer  and  Voit  later  modified  their  opinion; 
Fr.  Voit  again  discussed  the  experiments  in  detail  and  came  to  the  conclusion 
that  in  severe  diabetics  the  demand  for  calories  is  not  increased.  This 
result  is  entirely  in  agreement  of  the  long-protracted  metabolism  experiments 
of  Wientraud  carried  out  at  Nannyn^s  clinic.  H.  Leo,  R.  Stiive,  Xehring  and 
Schmoll,  and  Magnus-Levy  and  Salomon  have  further  instituted  experiments 
with  the  Zuntz-Geppert  apparatus.  They  found  that  in  severe  diabetics 
the  oxygen  requirements  were  increased.  I  shall  not  enter  into  the  question 
of  the  experiments  of  Livierato  and  of  Robin  and  Binet,  as  the  methods  used 
are  not  reliable. 

The  interest  in  this  question  was  reawakened  through  the  demonstra- 
tion that  there  was  an  increase  in  the  production  of  calories  in  the  dog 
without  a  pancreas.  Since  this  is  true  a  series  of  experiments  have  been  pub- 
lished. Of  especial  interest  is  a  great  number  of  experiments  that  were 
carried  out  in  Atwater-Benedicfs  respiration  calorimeter.  Finally  I  men- 
tion a  series  of  experiments  carried  out  by  Eugene  DuBois  and  Borden  S. 
Veeder  with  Pettenkofer's  apparatus  at  Kraus's  clinic,  and  finally  experi- 
ments with  the  Zuntz-Geppert  apparatus  by  Leimdorfer.  I  shall  discuss 
later  the  experiments  last  mentioned.  The  experiments  of  Eugene  DuBois 
and  Borden  S.  Veeder  showed  no  increase  in  heat  production.  These  authors 
arrived  at  the  same  results  as  did  Pettenkojer  and  Voit. 

A  more  exact  exposition  is  demanded  by  the  first-mentioned  experi- 
ments carried  out  in  the  respiration  calorimeter.  They  were  begun  by 
Benedict,  Dr.  Joslin  and  myselj  in  collaboration,  when  I  had  gone  to  Boston 
for  the  study  of  the  respiration  calorimeter.  Our  work  in  common  concerned 
itself  with  the  first  twelve  experiments.  I  reported  briefly  concerning 
these  experiments  at  the  Congress  for  Internal  Medicine,  1909;  and  there,  on 
the  ground  of  the  comparison  of  the  figures  obtained  with  those  obtained 
with  a  normal  subject,  whom  I  had  especially  selected  for  comparison  on 
account  of  his  low  body  weight,  came  to  the  conclusion  that  the  resting- 
exchange  of  the  three  diabetics  investigated  by  us,  and  especially  that  of  one 
very  severe  case,  was  not  essentially  raised.  Later  Benedict  and  Joslin  on 
the  ground  of  their  more  numerous  experiments  came  to  another  assump- 
tion.    Since  that  time  I  have  let  the  matter  rest  on  account  of  other  work. 


532  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

Only  now  at  the  preparation  of  this  chapter  have  I  received  the  experiments, 
and  also  the  large  experimental  material  of  Benedict  and  Joslin,  and  have 
attained  the  conviction  that  I  must  hold  fast  to  my  original  opinion.  As 
the  question  is  of  importance,  I  shall  contribute  the  first  twelve  experi- 
ments, that  Prof.  Benedict  has  in  praiseworthy  manner  allowed  me  to  pub- 
lish separately  in  extenso.  There  will  be  found  in  them  some  details  that 
seem  to  me  to  warrant  an  exact  exposition. 

First,  a  few  remarks  concerning  method.  The  experiments  herewith  published  w-ere 
carried  out  in  a  so-called  calorimeter.  Therefore  in  the  fasting  experiments  we  were 
concerned  with  estimation  of  the  exchange  in  a  quiet,  comfortable,  sitting-position.  It  is 
to  be  expected  that  the  values  obtained  in  the  fasting-experiments  do  not  fully  represent 
the  fundamental  exchange,  but  lie  somewhat  higher.  The  figures  republished  by  me 
differ  somewhat  here  and  there  from  those  in  the  corresponding  experiments  of  Benedict 
and  Joslin.  I  cannot  state  the  reason  for  this,  the  differences  are  however  so  slight  that 
they  do  not  influence  the  total  result  in  any  way.  As  concerns  the  exact  details  of  the 
arrangement  of  the  experiments,  I  refer  to  the  work  of  Be)iedici  and  Joslin.  In  the  tables 
will  be  found  the  heat-production  as  well  as  the  heat-elimination.  The  values  for  the 
heat-elimination  were  estimated,  by  adding  to  the  value  shown  by  the  calorimeter,  also  the 
vaporization  heat  of  the  water  produced  (amount  of  produced  water  0.568).  The  cal- 
culation of  the  heat  production  was  based  on  the  behavior  of  the  body-temperature. 

If,  for  example,  the  body  temperature  during  an  experiment  rose,  there  was  added  to 
the  amount  representing  the  elimination  of  heat  an  amount  that  would  be  necessary  to 
warm  the  person  under  experimentation  the  corresponding  tenths  of  a  degree.  If  the 
temperature  fell,  the  loss  of  heat  had  to  be  subtracted  from  the  figures  representing  heat 
elimination.  Ideal  values  for  the  heat  production  we  do  not  find,  however,  as  the  indi- 
vidual organs  may  possess  different  temperatures,  and.  for  example,  after  ingestion  of  food 
the  fall  of  heat  from  the  liver  to  the  mouth  or  rectum,  where  the  temperatures  are  taken, 
ought  to  be  greater  than  during  fasting.  Perhaps  this  is  the  reason  that  Benedict  and 
Joslin  do  not  giv^e  values  for  heat-production  in  their  experiments. 


Experiment  Xo.  I. — Person  inder  Experimentation"  .V 


Dextrose 


Date  Period  gj    !  P°'^- Titra-     *'^'    ■^•^'    *-°'  !   "'      ^'^^    ^'^      «    I  |~^ 


nza- 
<  "'    '  tion 


Nov.  4,  1908    '   Preceding  period 

7-  8  o'clock  .  .  .  .     84.5  2.19  2.430.514.77 I I I I J I 

f        8-10  o'clock'.  ...   186. 1  4.8  5.32  1.08  4.92 i ■  •  •  •! 

Fasting -j      10-12  o'clock 169.7  1.2  4. 901. 044. 71    38.740.20.70158.0    80     135.8. 

i2-2o'clock 118. 3  3.2  3.360.81  4.15    38.540.10.69941.4    81     137.6. 


-1 


Sum  from  lo  to  2  o'clock 288.0 8.  26  i  .85  ...  .     77.  2  80.3 273.42 


»  The  first  period  of  8  to  10  o'clock  I  have  omitted,  as  the  values  in  comparison  with  those  in  the  later 
fasting-experiments  were  non-serial.  Probably  the  patient,  who  was  in  the  apparatus  for  the  first  time,  was 
restless. 

2  Calculated  for  six  hours,  409.1. 


GENUINE    DL-VEETES    MELLITUS 


533 


Experiment  No.  II.- — Person  under  Experimentation  A 


Dextrose 


Date 


Period 


3  <u 
o  c 


Pola- 
riza- 
tion 


Titra- 
tion 


D:N 


CO2     O 


R.Q.   H2O 


as 


ffi 


W-a 


I  I 

Nov.  5,  1908  ,      Preceding  period    |  i 

220  gm.            7.24-  9 .  22  o'clock  303 . 1     7-9  '   8.9l'i.46  6.l 

meat        [     8. 22-10.28  o'clock  210. i     6.7       7-0     i.i     6.33    42.9  ■■••| 128.6    84   ' ii4S-7 

N=         1    10.28-12.28  o'clock  328.6  10.6      9.781.495.04    43.9  44.3I0.721J42.4    82     148.8 

10.22  gm.  I   12.28-   2.280'clock   184.2     5.2       5-65  1.394.04    41.0  43-9!o. 68033. 1     81     |r40.9 


Sum  (urine  from  about  3  hours) ,22.5     22 .  43  3 


127-8 I 435-4 


Experiment  No.  III. — Person  under  Experiment.ation  A 


Dextrose 


Date 


Period 


d  0) 
o  c 


Pola-i 

riza- 

tion 


Titra- 
tion 


D:N 


CO2  I   O2 


R.Q. 


H2O 


Eg 


as 


Nov.  18,  '08        Preceding  period 

7       -  8.52  o'clock   102.2    3. 
8.52-10.52  o'clock     97.9    2.94 


Fasting. 


3-87 
3-45 


0.80 
0.80 


4.84 
4-31 


10.32-12.52  o'clock     58.7     1.29 
12.52-  2.52  o'clock     so. 2    0.60 


Sum 


206.8    4.83     5.77  1.90 


1.36:0.55 


0.96'o.55'i.74 


38.5 
37.8 
37.9 


114. 2 


38.2  0.721 
40. 7  0.677 


47.9    69    98.1  138.6     139 
98.1  j 

36.3     67     '135.9   |l34 

I  98.0  I 

45.8.   65     131-5    |i27 

97.8 

406 . o    400 


Experiment  No.  IV. — Person  under  Experiment.\tion  A 


Date 


Period 


o  c 


Dextrose 


Pola- 
riza- 
tion 


Titra- 
tion 


D:N 


CO2 


R.Q. 


H2O 


P,^        aJ  o 


Nov.  19,  '08    I      Preceding  period 

fl   7       -  8.50  o'clock '117. o[   3.74'   3.900.85 


237  gm.  j 
meat  =  ! 
9.91  gm 

N 


.50-10.50  o'clock   297. 3^10. 01  10.23  1.87  5-47     44-8!   43-3  0.753    '50.872 


;  10.  50-1 2.  50  o'clock  '193.5 
;'l2.50-  2.50  o'clock  1134.4 


Sum 


6. 19 
3   76 


6.70  1. 58:4.24    45.4    46.50.709    53.368 
4.251.383.08    42.2    44.00.69S    45.766 


....   155.8 
98.  5 

156.9 

98.6 

151.3 


169 


625.2  19.96  21.18  4.83  ...  .132.4  133-8  0.719'    464.0    460 


Average. 


534 


DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 
Experiment  No.  \'. — Person  uxder  Experimextatiox  A 

^  Dextrose  I        r  — 


Date 


Period 


oc   1  P°la- Titra-'    N     D:N    CO2  j    O2       R.Q.     H2O   J    go,  -'^     %^ 


^  =1      tion 


Oh     H-2        K--         ffi-O 


Nov.  23,  '08         Preceding  period  !  '  ' 

7       -  9.20  o'clock     68.4,   3-42    403  o. 59  6.7     72 


75  gm. 
roll  +  25 

gm. 
dextrose 


9.  20-1 1.  20  o'clock  231.817.62 

ri.20-  1.20  o'clock   189.514.59 

1.20-  3.200'clock     99. S|   7-17 


Sum , I520.8  3938 


18.45  1. 13 

15.440. 99 

7.90|0.64 


97 

42.4    41.40.745       S8.8  72  98 

I       98 

38.3    38.7  0.720      52.9  68  .  . 

97 

37.3    37.1  0.730       48.5  64  .  . 

i  !  97 


o  153"  154 
o 

•  141-8  137 

8 

.   132.  I  128 


41.792.76....   118.0  117.  2  0.7321    427.6419 


Experiment  Xo.  VI. — Persox  under  Experiment.ation  A 


Dextrose 


Date 


Period 


gg   {  Pola- .pj^j.^.     N     D:N    CO2  ]    O2 


R.Q.  I  HsO 


Nov.  24,  '08       Preceding  period 

7        -9.200'clock   175.6    5.27    7.461.236.06 

'  i 

75  gm.        I   9. 20-1 1 .  20  o'clock  237.6  16.63  17.73  i.ii].... 

roll  +  25  I  I  ! 

gm.  dex-    J    11.20-  l.20o'clock  214.2  15.85  16.32  i  .04  ...  . 
trose 

1 .  20-  3 .  20  o'clock  108.5    7.27    7.920.67I.. 


Sum 


70 


97.9 

39.8    42.20.687  58.87298.0    146.1147 
I              I  '      98.05; 

37.81   37.3j0.73S  53.967 135-7  I33 

I  I  ;       97-95  I 

37. 5    37.S|0.726   ,  49.1163 135.5132 

I  97.8 


560.3  39-75  41-97  2.82  ...  .115.1  li7.IO.7iS'   161. 


I417.3I412 


EX-PERIMENT    Xo.    MI. — PERSON  E'NDER  EXPERIMENT.VTIOX  B 


Date 


Period 


-           Dextrose  a^-. 

c  I    fegi 

gg  Pola- .pj^j.g_  X    |D:N    CO2       O2       R.Q.      H2O    J'    gg 

EC  riza-     .-  '                                                     -3     c  ^ 

<3  tion     "°^  1  '                                                    (X     H-P 


B 

<o  o 
Si  <^ 


Nov.  9,  '08  I     Preceding  period  |  | 

I  7       -  9-02  o'clock  241.3  10. 13  II  .49  1.87 


f     9.02-11 .02  o'clock  136.6    5.46    6.02 
Fasting..    I    11.02-  1.02  o'clock     91.5     2.74    3.81 
1.02-  3.02  o'clock     62.9    1. 31    2.14 


6.13 


1.244.83   51.01  so. 90. 729     46.577 


98.7 


l.003.82[   47. 5    49.40.699      59-177 


98.45 


0.90:2.43    45.9!   46.60.717       S3.' 


176.3  167 
171. 7  167 
160. I  170 


98.95 


Sum 


291.0     9-51  11-97  3-  14  -  •  -  -   144-4  146-9  0.715'    5o8 .  i  504 


'  Average. 


GEXriXE    DIABETES    MELLITUS 
ExPEEiiiEXT  Xo.  VIII. — Persox  uxder  Experimextatiox  B 


535 


Date 


Period 


Dextrose    ; 


i-S      riz^Tltra- 
^  3      tion     *'°^ 


X     D:X    COi       O2       R.Q.      H2O    p      rT 


2  ei  ^ 


Nov.  10,  '08      Preceding  period 

8       -  8.540'clock  214.7 8.461.038.2 


j  j    8. 54-10. 54  o'clock  218.9 7.421.07^7.0      53.7     57.30.682       41.9  77  .....  194.3  196 

I                                                                                                                                                          98.9 
Meat      )  '10.54-12  .54  o'clock  268.8 9.952.124.7       54.2     57.7  0.683       67.2  77 190. 1:193 


99.0 


12.54-  2.54  o'clock   168.2 •.     7.012.143.23     58.3    59.30.715   ■:   4S-9 

i  '■ 


Sum 655  .  9 


24.38  5.33 


166.2  1743  0.693^  1550 


193-6  169 


578.0558 


ExPERniEX'T  Xo.  IX. — Persox"  uxder  Experihextatiox" 


Date 


::  Dextrose 

Period              I    §0  pola-  ^.,         N     D:X    CO2       O2       R.Q.     H2O 

s  j-  i  ^^-     tion 

<  S  ,  tion 


e-S     H-s 


Nov.  16,  '08       Preceding  period 

!    7       -  9.21  o'clock  266.2  15. 17  14. 152. 266. 26 82 

f     9.  21-11 .21  o'clock   152.6     7.02     7.3211.49  4.88' I 46.48099.0     162.0 

i  I  I  I  i  i      !98-5 

Fasting.  .    i    11.21-  1.21  o'clock   105.4    4-22     4.75  1.25:3. 80 44.2  79 159-9 

j  98.3 

1 .21-  3.21  o'clock   161 .2     2  .  10     2  .53  o.  85  2  .98 46.4  80 156.7 

98.6 


Sum 419.2  13.34  14.60  3. 


137-0 


47S. 


ExPERIiEEX'T    Xo.    X. PeRSOX'  TTXTJER  ExPEE nrF.NTATIOX"  B 


Period 

l'§ 

Dextrose 

N 

D:N    CO2 

O2 

R.Q. 

0 
Pulse 

Tempera-^ 
ture  (P.) 

II 

ft.2 

■s'l 

Date 

1 

^°i^-Titra-: 
Itio^"     tion: 

Nov.  17,  '08 

Preceding  period 

I 

i 

1 

7       -  8.07  o'clock  127.0    7. II    7. 190. 92  7.  82 

II 

8.07—  9.26  o'clock  165  .4    8.93    9.57  1.26.7.60 90 

I.  Chief    I      7  .26-11.26  o'clock  275.3  19.15  14.37  2. 26|6. 36    52.0    54.10.699      60.08399.0 
period      i  98 . 5 

meat,      j    11.26-  i  .26  o'clock  215.7  10.04  11.04  2.20  5.0      52.0    53.7  0.705       58.4  76 

16.9  gm. 
N 


98.3 


i    1 .  26-  3 .  26  o'clock   165.0     8.13     8.483.102.74    55.2     57.60.697       60.280 


174-3  160 
173-7  168 
173.8  177 


Sum 


656.0  37-32  33    89  7-56  -  .  .  .   159-2  165.40.7001   178.6 52I-8  505 


1  Average. 


536  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

Experiment  Xo.  XI. — Person  untjer  Experimentation  C 


Date 

Period 

5  0 
0  c 

'    Dextrose 

P°!f- Titra- 
tion    *•- 

X 

D:X     CO; 

O2 

R.Q. 

a '-5 

cS  0 

0  3 

ffi-c 

Nov.  11-12. 

Preceding  period 

I 

1 

1908. 

7       -  8.50  o'clock  86.8    2.34    2.66  1. 19  2.23 

'     8.50-10.50  o'clock  95-4     1-72     1.941-381.4      48.9    46.80.759    46.8    8298.6     181. 7  172 
I  98.2 

Fasting..    :    10.50-12 .  50  o'clock  69.7    0.56    0.841.090.76    47-5     45-8o.753    43-8    81 161. 7162 

i  98.2 

12.50-  2.50  o'clock  55-2    o.ii    0.280.930.29    47.4    52.10.661     52.1     80 157.116s 

98.5 


Sum 


220.3     2.39     3   06  3   40  0.9'    143.8  144- 7  0.722 1    500.5  499 


Experiment  Xo.  XII. — Person  under  Kxperiment.ation  C 


Date 


Period 


Dextrose 
2     Pola- 


<  3      tion 


!    N     D:X    CO:       O2       R.Q.      H2O    o      o.--"  1^  §    L.-B 
„„      Titra-  .2     E  £      Ij-^   I  CS  o 


tion 


CL,    E--^     Mc     ffi-o 


Xov.  12-13,       Preceding  period 
1908. 

7       -  8.58  o'clock   142.4    5-13    5  40  1-95  2.7     

'    8.58-10.58  o'clock  272.5  10.90    9-8l3ll3-l6    59-7     59-20.734    423     88992     199.9184 
Meat  98.6 

17.39  10.58-12.58  o'clock  244.0    9.7610.223.582.56    59.8    58.40.744    66.6    89 196.5207 

gm.  X.  99.0 

12.58-  2.58  o'clock   157-2     5.66     5.81  307  1-9       57-4    57-80.722     46.1     87 191. 8  176 

98.4 


Sum 


25.84  9-76 


176.9  175.4  0.733'   588.2  567 


The  Fasting  Experiments 

The   rest-fasting   experiments    are   summarized   in    an   easily   re\-iewed 
manner  in  the  following  table : 

Rest-f.\sting  Experiments 


Person  under  ex- 
periment 


Date        Age     ^ 


D:X 


C02 

0. 

Per 

Per        kg. 

hr.         and 

min. 

Per 

and 
min. 

Calories 


R.Q. 


No.  I.  A Xov.  4...    47I49.1    171      (4.77)-4.92      3.344.76    0.688 

Diabetes  mellitus  —4.71-4 

Xo.  III.  A Xov.  18.     47  52.8,  171      (4.84)-4 

■|  I-3-0-I 

No.  VII.  B Xov.  9 60.0   173      (6.i3)-4 

Diabetes  mellitus  —3.82-2 

No.  IX.  B Xov.  16.    ...   60.0   173      (6.24)-4 

Diabetes  mellitus  —3.80-2 

Xo.  XL  C Xov.  II..    23  59.2    176      (2.23)-i 

Diabetes  mellitus  —0.76-0 

Average 3.  26  4.59 

A.  W.  \V.  normal     Mar.  21 57.0 3.65  4.38    0.832 

A.  W.  \V.  normal     ilar.  15 57.0 3.65  4. 10    0.840 


.31       19.37  3.06  4.34  

74 
•83       24.07  3.36  4.76  

•43 

22.52  3.14  4.33 

.40       23.93  3.40  4.76    0.722 
29 


1-34 

76.55   1-35 
76.55   1-37 


'  Average. 


GENUINE    DIABETES    MELLITUS  537 

I  laid  these  tables  before  the  congress  in  my  communication.  It  will 
readily  be  understood  why  I  on  the  data  of  these  experiments  believed  that 
there  was  an  essential  increase  in  the  production  of  calories  in  diabetes 
mellitus. 

The  production  of  calories  per  kg.  per  hr.  is  on  the  average  in  the  diabetics,  1.34,  in  the 
normal  person,  1.345;  the  oxygen  consumed  is  in  the  diabetic  greater  throughout.  It  is 
on  the  average,  4.59,  in  the  normal  person,  4.24. 

I  shall  speak  later  as  to  the  cause  of  the  greater  oxygen  consumption  in 
diabetics. 

The  carbonic  acid  production  is  on  the  average  in  diabetics  3.26,  in  the  normal  person, 
3-65- 

Hence  the  production  of  carbonic  acid  is  somewhat  less  in  the  diabetics. 

The  respiratory  quotient  is  very  low  throughout  in  the  diabetics,  cor- 
responding to  the  circumstance  that  all  the  cases  investigated  were  moder- 
ately severe  cases.  Also  the  person  C  may  be  counted  with  the  moderately 
severe  cases. 

The  question  that  I  asked  myself  at  the  reworking-up  of  the  experiments 
was  the  following:  Do  there  exist  severe  cases  of  diabetes  mellitus  that  in 
spite  of  the  copious  elimination  of  sugar  show  no  increase  in  heat  production 
during  fasting?  As  there  were  only  a  relatively  few  experiments  at  my 
disposal  for  the  solution  of  this,  conclusions  as  to  the  question  were  merely 
tentative.  The  diet  which  the  persons  tested  received  on  the  days  be- 
fore the  experiments  were  mixed.  It  contained,  however,  neither  abun- 
dant carbohydrate  or  protein.  As  all  experiments  began  fourteen  hours  after 
the  latest  ingestion  of  food  and  lasted  six  hours,  so  that  the  experiment  lasted 
for  the  fourteenth  to  twentieth  hours  after  the  latest  ingestion  of  food,  the 
quotient  D :  N  observed  must  be  regarded  as  high.  Only  in  person  C  did  the 
quotient  D :  N  fall  almost  to  o  during  the  period  of  experimentation.  In  the 
first  persons  under  experimentation  the  ammonia  value  was  also  raised  very 
high.  In  person  A  the  ,8-oxybutyric  acid  in  the  urine  was  also  estimated 
and  found  in  not  inappreciable  quantity.  I  have  not  included  these  figures 
in  the  tables  and  refer  to  the  detailed  works  on  Benedict  and  Joslin.  In  such 
severe  cases,  as  persons  A  and  B  are,  one  must  expect  under  conditions  of 
experimentation  that  there  would  have  been  an  appreciable  result,  if  the 
heat  production  in  severe  diabetes  is  really  increased.  It  was  not  the  case, 
however.  We  have  already  seen  previously  that  the  chemical  observations 
allow  this  result  to  be  anticipated. 

On  the  study  of  the  extensive  and  carefully  detailed  experimental  material 
contributed  later  by  Benedict  and  Joslin  I  have  arrived  at  the  conviction 
that  an  increase  of  heat  production  in  diabetes  mellitus  cannot  be  inferred 
also  from  this  material.  The  explanation  of  the  deviating  conclusions  of 
Benedict  and  Joslin  is  to  be  sought,  I  think,  in  the  fact  that  they  did  not  take 


538  DISEASES    OF    THE    IXSULAR   APPARATUS    OF    THE    PANXREAS 

into  account  the  difference  in  body  weights  of  the  normal  persons  and 
diabetics  they  investigated.  I  here  quote  in  descending  series  the  body 
weights  of  the  normal  individuals  and  the  diabetics. 

Normal  individuals:  83.5-79.7-74.4-67.6-66.5-66.0-59.6-48.5. 

Severe  diabetics  (weight  during  the  experiment):  67.1-59.0-54.9-52.7- 
51.8-48.8-48.0-40.5. 

A  glance  at  this  summary  shows  the  great  difference  in  body  weight 
between  the  normal  and  the  diabetic  individuals. 

When  we  compare  with  one  another  the  heat  production  of  those  cases 
that  have  the  same  body  weight,  we  obtain  the  same  result  that  I  found  in 
the  preceding  experiments.     This  is  seen  in  the  following  summary: 

Mrs.  B. 

Weight 67.0 

Height 161 .0 

Calories  per  kg.  per  hr i .  09 

L.E.E. 

Weight 59.6 

Height 1790 

Calories  per  kg.  per  hr i  .47 

Dr.  R. 

Weight 48.5 

Height 167.0 

Calories  per  kg.  per  hr 1.39 

The  heights  of  the  persons  under  experimentation  are  not  entirely  alike. 
In  the  cases  of  Mrs.  B.  and  diabetic  G  the  difference  is  indeed  appreciable. 
In  the  other  two  pairs  the  dift'erence  would  not  signify  much.  In  addition, 
in  one  case  the  difference  favors  the  normal  individual,  in  the  other  it  favors 
the  diabetic.  We  see  from  this  summar}'  that  the  heat  production  in  cases  of 
severe  diabetics  does  not  dijfer  essentially  from  that  of  the  equally  heavy  normal 
individual. 

Benedict  and  Joslin  themselves  made  the  objection  that  their  material 
is  not  uniform  in  respect  to  body  weights.  They  sought  to  rule  out  this 
objection  in  the  following  experiment  (Case  C.  S.,  227).  The  first  investiga- 
tions were  undertaken  at  a  time  that  the  patient  weighed  62.4  to  65.4  kg. 
They  found  at  that  time  a  heat  production  between  1.23  and  1.40  per  kilo- 
gram per  hour.  As  the  patient  had  later  fallen  away  to  54.9  kg.,  the  heat  pro- 
duction (in  one  experiment)  was  1.26  per  kilogram  per  hour.  I  can  ascribe 
to  this  one  experiment  no  demonstrative  value.  It  is  a  known  law  that  in 
normal  individuals  the  exchange  lies  higher  the  smaller  and  lighter  the  indi- 
vidual is.  This  is  readily  seen  from  the  figures  that  Benedict  and  Joslin 
themselves  have  summarized. 


Diabetic  G 

67  .0 

178.0 

1 .  15  (bed  calorimeter) 

Diabetic  F 

590 

176.0 

1-39 

Diabetic  A 

48.8 

171 .0 

1-34 

GENUINE    DIABETES    MELLITUS  539 

Investigations  with  Zuntz-Geppart  apparatus  (p.  i68): 

Individuals  between  65  and  43.2  kg.   O2  requirements  per 

kg.  per  minute 4.08  c.c. 

Individuals  between  66  and  88.3  kg 3.5    c.c. 

Investigations  with  the  respiration  calorimeter,  during  sleep  (p.  i68) : 

Individuals  between  64.1  and  55  kg 4.04  c.c. 

Individuals  between  66.1  and  84.7  kg 3  •  S6  c.c. 

There  does  occur  in  severe  diabetes  a  circumstance  moreover  that  must 
be  considered  especially.  It  is  known  that  in  the  obese  the  fundamental 
exchange  is  relatively  low,  as  the  obese  person  possesses  little  respiring  proto- 
plasm in  relation  with  body  weight.  The  severe  diabetic  is,  however,  always 
strongly  drained  of  water  (as  is  shown  in  investigation  on  the  water-con- 
tents of  the  organs  of  those  dying  in  coma) .  Moreover,  in  severe  diabetics 
almost  every  trace  of  fat  has  disappeared  from  the  ordinary  sites  of  fat-de- 
position, as  can  be  seen  at  almost  every  autopsy.  If  now  in  addition  the 
albuminous  constituent  suffers  severe  damage  in  the  later  stages,  the  mass  of 
respiring  protoplasm  in  severe  diabetes  will  be  still  greater  in  proportion 
to  body  weight.  I  believe,  therefore,  that  even  if  on  calculation  per  kilo- 
gram of  body  weight  there  is  found  in  severe  diabetics  a  slight  increase  of 
heat  production,  this  would  not  mean  much. 

Already  Lw5^  has  pointed  out  the  dissimilarity  of  the  material  compared 
by  Benedict  and  Joslin,  and  from  this  has  drawn  the  conclusion  that  the  in- 
crease of  heat  production  found  by  Benedict  and  Joslin  is  less  high  than  these 
authors  suppose.  From  the  calculations  and  discussions  cited  I  must,  however, 
conclude  that  the  demonstrations  of  an  increase  of  heat  production  in  severe 
diabetes,  has  with  the  material  at  hand,  not  been  supplied.^ 

Now  as  concerns  the  oxygen  requirements,  this  in  severe  cases  of  diabetes 
is  undoubtedly  increased.  This  may  be  seen  in  my  tables.  I  find  that  the 
oxygen  requirements  with  otherwise  similar  heat  production  average  in  the 
diabetics  4.59,  in  the  normal  individuals  4.24. 

I.  This  is  also  to  be  seen  in  the  figures  of  Benedict  and  Joslin:''  That  there 
is  an  increased  heat  production,  however,  cannot  be  inferred  from  the  in- 
creased demand  for  oxygen.  Already  Leimddrfer  mentioned  that  in  the 
severe  diabetic  through  the  loss  of  bodies  very  rich  in  oxygen,  in  the  urine 

^Remark  on  Correction. — Also  in  a  second  publication  that  Benedict  and  Joslin  made  a  short 
time  ago  concerning  this  subject  (A  Study  of  Metabolism  in  Severe  Diabetics,  Carnegie  Institu- 
tion of  Washington,  Publication  No.  476,  191 2),  this  is  shown  in  an  indubitable  manner.  Here 
are  found  statements  only  as  to  the  carbonic  acid  production  and  the  oxygen  requirements; 
in  the  severe  diabetics  there  was  a  CO2  elimination  ,(pcr  kg.  per  min.)  of  3.13  c.c.  (according 
to  my  calculation  3.25);  in  the  normal  individual  of  like  weight  this  was  3.13- 

-  In  the  second  publication,  4.54  O2  per  kilogram  per  minute  in  the  severe  diabetics  as  against 
3.75  in  normal  individuals  of  the  same  weight. 


540  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

(sugar,  ketone  bodies),  the  relation  between  oxygen  consumption  and  car- 
bonic acid  production  is  disarranged.  Direct  calorimetry  actually  shows  in 
the  experiments  made  at  the  Boston  Institute,  that  in  diabetics  with  normal 
heat  production,  the  oxygen  consumption  is  increased. 

2.  In  the  experiments  with  the  administration  of  meat  the  specific  dynamic 
energy  of  the  protein  and  the  time  consumed  in  the  decomposition  of  this 
in  severe  diabetes  was  investigated.  The  question  can,  however,  scarcely 
be  discussed,  because  the  number  of  experiments  is  too  small. 

3.  The  experiments  with  the  administration  of  carbohydrates'  seem  on 
the  contrary  to  be  worthy  of  mention.  In  these  investigations  there  was 
sought  to  be  determined  whether  in  short  periods  (two  hours)  the  respira- 
tory quotient  did  not  temporarily  rise.  The  two  experiments  on  this 
subject  agree  very  prettily.  In  normal  individuals,  on  the  administration 
of  just  as  much  carbohydrates,  we  would  expect  an  increase  of  the  respira- 
tory quotient  to  nearly  i.o.  In  the  two  experiments  on  the  diabetic  the 
respiratory  quotient  was  hardly  influenced,  however.  In  the  severe  diabetic, 
therefore,  the  administration  of  carbohydrates  does  not  suffice  to  increase  the 
combustion  of  sugar.  These  experiments  agree  very  prettily  with  the  ex- 
periment of  Falta,  Grote,  and  Staehelin  on  the  dog  without  a  pancreas.  Also 
here  the  respiratory  quotient  was  not  increased  on  the  administration  of 
sugar.  In  both  experiments  on  the  diabetic  the  heat  production  rose  some- 
what in  the  first  two-hour  periods.  This  rise  is  perhaps  to  be  referred  to  the 
increased  work  of  digestion. 

The  manifestations  on  the  part  of  the  vegetative  nervous  system  in 
diabetics  has  only  recently  been  made  the  subject  of  study.  I  have  already 
in  the  discussion  of  the  experimental  physiology  mentioned  LdivVs  reaction. 
Its  absence  shows  an  increased  excitability  of  the  dilator  pupillae  (innervated 
by  the  sympathetic).  We  have  tested  this  reaction  in  human  diabetes  on 
a  large  amount  of  material  and  have  found  it  positive  in  a  number  of  cases. 
We  could  not  demonstrate  that  it  is  connected  with  the  intensity  of  the 
glycosuria  or  ketonuria.  We  sometimes  found  it  positive  in  cases  in  an 
aglycosuric  condition,  and  in  other  severe  cases;  even  in  the  presence  of 
coma,  it  was  negative.  The  glycosuric  action  of  adrenalin  in  diabetes  has 
been  studied  by  Newbiirgh,  Nobel,  and  myself.  It  was  found  that  in  cases  in 
the  aglycosuric  state,  adrenalin  in  almost  all  cases  leads  to  a  distinct  increase 
in  the  elimination  of  sugar.  On  the  contrary,  in  a  certain  number  of  these 
aglycosuric  cases,  the  action  was  negative.  There  were  among  these  cases 
that  had  to  be  regarded  as  severe,  cases  that  only  on  the  complete  withdrawal 
of  the  carbohydrate  and  strong  limitation  of  the  protein  would  be  main- 
tained sugar-free,  and  that  on  the  administration  of  slight  amounts  of 
carbohydrates  responded  with  glycosuria.  These  investigations  show  the 
independence  of  the  nervous  and  alimentary  factors  at  least  in  the  aglycosuric 
state.     An  especially  intense   action  of  the  adrenalin  on  the  heart  and 


GENUINE    DIABETES    MELLITUS  541 

vascular  system  in  diabetes  could  not  be  shown.  On  the  contrary,  among  the 
cases  investigated  were  a  number  in  which  enormous  adrenalin-diuresis 
supervened.  Among  the  numerous  non-diabetes  cases  on  whom  we  tested 
the  diuretic  action  of  adrenalin,  we  never  saw  an  action  so  intense.  It  is 
especially  worthy  of  remark  that  among  the  diabetics  who  resisted  so  in- 
tensely, were  also  cases  in  an  aglycosuric  condition.  Therefore  in  many  a 
diabetic  the  vessels  of  the  kidneys  are  in  an  abnormally  irritable  state,  [a  fact] 
which  was  not  known  before.  I  might  take  advantage  of  this  opportunity  to 
add  some  remarks  concerning  the  diuresis  in  diabetes  mellitus.  Ordinarily  we 
find  a  parallelism  between  the  intensity  of  the  elimination  of  sugar  and  the 
amount  of  the  urine.  It  has  been  known  for  a  long  time  that  there  are  ex- 
ceptions to  this  rule.  There  are  cases  in  which  a  long  period  of  increased 
diuresis  precedes  the  occurrence  of  diuresis  {v.  Noordeji).  There  are  further 
cases  in  which,  as  v.  Noorden  likewise  emphasizes,  the  polyuria  outlasts  the 
glycosuria  for  a  long  period.  Then  there  are  cases  in  which,  in  spite  of  high 
percentage  of  sugar,  the  amount  of  urine  is  very  slight.  Naunyn  reports,  for 
example,  a  case  in  which  about  8-9  per  cent,  of  sugar  was  excreted,  with  2 
liters  of  urine.  In  another  case  there  was  just  as  much  sugar,  and  a  specific 
gravity  of  1040,  with  urine  amounting  to  only  1 200-1400  c.c.  We  designate 
these  cases  diabetes  decipiens.  On  the  other  hand  there  are  cases  with  con- 
siderable polyuria  with  relatively  little  elimination  of  sugar,  especially  if 
the  diabetes  came  as  a  result  of  head  injury.  Naunyn  reports,  indeed,  a  case 
of  pure  uncomplicated  diabetes  who  constantly,  with  a  diuresis  of  5-6  liters 
eliminated  only  1.2-2  per  cent,  of  sugar.  Hence  the  elimination  of  sugar 
is  certainly  not  the  only  cause  of  the  increased  diuresis,  and  perhaps  not 
the  principal  cause.  According  to  the  experiments  previously  mentioned  the 
increased  diuresis  has  its  foundation  in  an  especial  sensitiveness  of  the 
kidney  vessels  to  an  irritant  circulating  in  the  blood.  We  can  summarize 
the  observation  set  forth  in  the  statement  that  in  many  cases  of  diabetes 
mellitus  a  heightened  excitability  of  certain  organs  innervated  by  the  sympathetic 
{dilator  papillce,  liver,  kidney,  etc.) ,  may  eventually  also  exist  in  the  aglycosuric 
condition. 

The  excitability  of  the  autonomous  nerves  in  diabetes  mellitus  is  not 
diminished  throughout.  We  have  even  in  numerous  experiments  in  the 
advanced  stage  of  diabetes  found  strikingly  intense  actions  of  pilocarpine 
on  the  secretion  of  sweat  and  saliva.  Also  the  miotic  action  of  pilocarpine 
is  very  distinctly  pronounced.  That  the  diabetic  glycosuria  is  not  diminished 
by  pilocarpine,  is  here  mentioned  because  the  fact  again  illustrates  the  in- 
dependence of  the  nervous  and  alimentary  factors.  In  advanced  cases  there 
are  found  many  kinds  of  manifestations  that  perhaps  may  even  point  to  a 
heightened  irritability  in  many  territories  of  the  autonomous  nervous 
system.  We  observed  in  almost  all  very  severe  cases  high-grade  obstipation, 
whose  spastic  nature  was  shown  on  the  palpation  of  the  sigmoid  flexure  and 


542  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANXREAS 

through  the  appearance  of  the  stools.  Up  to  the  present  I  have  not  seen 
similar  statements  in  the  literature.  Purgative  measures  are  of  service 
in  such  cases  only  when  they  are  given  in  rather  large  doses,  and  then  defe- 
cation is  rather  painful.  Such  patients  prefer  enemas  to  purgatives. 
The  spastic  nature  of  this  obstipation  is  demonstrated  too  by  the  prompt 
action  of  a  subcutaneous  injection  of  atropine  (i  mg.).  On  what  ground 
there  occurs  the  development  of  such  a  spastic  obstipation  is  difficult  to  say; 
it  can  hardly  be  due  to  the  lack  of  bread  in  the  diet,  as  these  cases  on  account 
of  considerable  ketonuria  could  not  long  have  been  kept  on  a  carbohydrate- 
free  diet,  and  the  diet  was  in  addition  always  very  rich  in  cellulose  (vegetables). 

I  would  further  mention  here  an  observation  which  I  have  like^^'ise  not 
been  able  to  find  in  the  literature.  We  found  in  all  severe  cases  of  diabetes 
in  which  the  examination  was  made,  a  relative  or  absolute  increase  in  the 
mononuclear  cells  in  the  blood.  As  the  total  count  of  the  leucocytes  was 
always  normal,  there  always  existed,  then,  a  relative  and  absolute  diminution 
in  the  number  of  neutrophilic  cells.  It  is  possible  that  chemotactic  influences 
lie  at  the  basis  of  this.  If  we  regard  this  as  in  connection  with  the  spastic 
obstipation,  we  could  consider  it  as  the  expression  of  a  high  tonus  of  the 
autonomous  nerves. 

I  would  not  leave  the  description  of  the  manifestations  of  the  vegetative 
nervous  system  without  mentioning  a  finding  that  probably  belongs  here. 
In  investigations  carried  out  together  with  Neivhurgh  and  Nobel,  we  found  on 
the  administration  of  tliyroidin  to  nondiabetic  individuals  a  reduction  of 
the  fall  of  blood-pressure  from  heart  to  periphery.  Investigations  on  the 
blood-pressure  in  the  brachial  artery  with  Riva-Rocci's  apparatus  showed  no 
change,  while  the  investigation  at  the  finger  with  Gj>/»f;''5  instrument  showed 
in  many  cases  a  distinct  fall  of  the  blood-pressure.  In  the  diabetics  we  found, 
however,  after  the  use  of  thyroidin  a  distinct,  and  in  many  cases,  an  appreci- 
able increase  in  blood-pressure  with  both  methods;  this  increase  often  out- 
lasted the  thyroidin  medication  for  days.  We  could  also  observe  this  in 
cases  in  the  aglycosuric  condition.  It  is  very  well  likely  that  this  increase 
of  blood-pressure  is  brought  about  through  an  enormously  increased  activity 
of  the  chromaffin  tissue.  If  this  is  so,  it  must  be  assumed  that  in  diabetes 
there  exists  an  enormously  increased  excitability  of  this  organ  or  of  the  nervous 
centers  regulating  its  activity. 

Also  the  erethism  of  the  vessels  of  the  skin  speaks  for  an  increased  ex- 
citability of  the  vegetative  nerves.  The  red  face  of  the  diabetic;  lending  as 
it  does  such  a  characteristic  appearance  to  the  advanced  case,  is  well  known. 
Also  there  mostly  exists  distinct  dermographism.  On  exposure  the  skin 
often  reddens  to  far  over  the  trunk.  It  is  known  that  the  skin  of  the  severe 
diabetic  is  often  very  dry  on  account  of  the  severe  draining  of  the  dry  body  of 
its  water,  yet  there  do  not  rarely  occur  sweats,  even  in  cases  that  show  no 
manifestations  of  a  complicating  tuberculosis  of  the  lungs. 


GENUINE    DIABETES    MELLITUS  543 

Finally  I  would  mention  a  group  of  diabetics  in  whom  the  conditions 
of  hyperexcitability  and  hyperirritability  of  the  sympathetic  nervous  system 
are  still  more  prominent.  These  are  for  the  most  part  diabetics  in  middle 
life,  who  overwork  much  and  who  in  their  occupations  are  exposed  to  great 
excitements  and  cares;  moreover,  they  may  have  sustained  traumas.  Psychic 
excitements  are  here  an  important  factor  in  the  influencing  of  the  glycosuria. 
The  blood-pressure  is  often  raised  not  inappreciably,  but  in  spite  of  this, 
traces  of  albumin  are  found  only  transitorily,  and  here  and  there  is  seen  an 
entirely  isolated  cast.  In  such  cases,  adrenalin  acted  glycosuric  in  the 
aglycosuric  state;  the  Lowi's  reaction  was  positive.  We  may  perhaps  desig- 
nate these  cases  as  hypertonic  diabetes. 

As  example  I  cite  the  following  case: 

Observation  LXIX. — G.  K.,  forty-eight  years  old,  conductor;  entrance  into  the  first 
medical  clinic  on  Sept.  6,  1912.  In  the  year  1904  the  patient  suffered  a  train  injury. 
In  it  he  was  thrown  to  the  floor,  and  the  right  thigh  was  contused.  In  July,  1910,  he  fell 
from  a  wagon,  immediately  after  which  he  had  the  sensation  as  if  something  internal  had 
torn.  Since  this  time,  always  sensitiveness  to  pressure  in  this  region,  and  very  nervous. 
In  191 1  unquenchable  thirst  with  decrease  of  the  previous  appetite.  The  skin  was  dry,  the 
potentia  coeundi  fell  off  very  much.  On  entrance  there  was  found  3.7  per  cent,  sugar  and 
a  distinctly  positive  acetone  reaction.  The  sugar-elimination  after  the  ingestion  of  75  gm. 
of  roll  and  a  third  of  a  liter  of  cream  was  about  80  gm.  dextrose,  the  excretion  of  acetone 
was  about  3  gm.  On  withdrawal  of  carbohydrates  the  sugar  sank  rapidly,  the  oat-meal 
treatment  that  was  instituted  brought  about  only  traces  of  sugar,  the  acetone  disappeared. 
The  tolerance  rose  very  quickly,  so  that  after  six  weeks  the  patient  bore  60  gm.  roll,  30  gm. 
rice,  and  60  gm.  potato  without  excretion  of  sugar. 

The  amount  of  urine  during  the  sugar-free  period  was  also  appreciably  increased. 
Mostly  there  were  values  of  2000.  At  the  beginning  also  values  between  3000  and  4000. 
The  specific  gravity  was  raised  only  in  the  first  day.  Then  it  sank  quickly  to  about  loio, 
and  later  showed  great  variations;  it  mostly  lay  low,  around  or  lower  than  loio,  and  tem- 
porarily would  increase  to  1020. 

The  patient  was  very  excitable,  the  patellar  reflexes  were  lively,  the  blood-pressure  was 
high,  varying  according  to  measurements  by  the  Riva-Rocci  apparatus  between  130  and 
150.  Correspondingly  the  arteries  showed  increased  tension,  but  there  were  no  signs  of 
arteriosclerosis.  The  heart  dulness  was  broadened  to  a  slight  extent  toward  the  left.  In 
the  urine  was  found  on  repeated  examinations  at  most  minimal  traces  of  albumin.  No 
casts  were  found  in  the  centrifugated  fluid.     Lowi's  reaction  was  positive. 

In  the  aglycosuric  condition  i  mg.  of  adrenalin  was  injected  many  times.  Regularly 
there  occurred  a  not  inappreciable  elimination  of  sugar,  once  to  6  gm.,  in  the  hours  after 
the  injection.  One  of  these  experiments  took  place  at  the  time  that  the  tolerance  of 
the  patient  was  already  essentially  increased.  Further  the  diuretic  action  and  especially 
the  action  on  the  heart  and  vessels  was  strongly  marked.  In  the  experiment  mentioned 
the  blood-pressure  rose  to  180. 

The  investigation  of  the  respiratory  gas-exchange  (Dr.  Bernstein)  always  showed  nor- 
mal CO2  production,  and  mostly  an  increased  O2  consumption.  The  gas-exchange  after 
an  adrenalin  injection  was  investigated  twice.  Both  times  the  oxygen  consumption  and 
carbonic-acid  production  rose  strongly,  but  the  respiratory  quotient  was  not  influenced. 
I  cite  the  following  experiment  as  an  example: 


544  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 


CO2  Per  kg.  per  min.  Oi  Per  kg.  per  min.  RQ 


217.6  2.75  317-71  4-02 


0.685 


Before 

20  min.  after  injection  of  i 
mg.  adrenalin 250.0    372.5     0.671 

In  this  e.xperiment  the  injection  led  to  an  elimination  of  6  gm.  of  sugar.  The  action  of 
adrenalin  was  therefore  intensive  in  all  respects,  only  the  raising  of  the  respiratory  quotient 
was  wanting. 

I  would  here  mention  quite  briefly  the  complications  of  diabetes  mellitus. 
In  diabetes  in  men,  impotence  is  one  of  the  most  frequent  complications; 
only  very  rarely  does  there  occur  increased  sexual  desire.  With  the  former  is 
often  found  an  atrophy  of  the  testicles.  In  the  diabetic  women,  men- 
struation is  disturbed  only  in  the  severest  cases,  but  on  the  contrary,  con- 
ception is  rare.  In  men,  there  is  never  observed  a  retrogression  of  the 
secondary  sexual  characters.  The  deleterious  influence  affects  therefore 
only  the  generative  part  of  the  function  of  the  sexual  glands.  The  vulnera- 
bility of  the  tissues,  the  falling  out  of  the  teeth,  the  suppurations,  diabetic 
cataract,  the  furunculosis,  the  xanthelasma,  the  pruritus,  the  rheumatoid 
pains,  the  diminution  of  the  reflexes,  and  the  degenerations  of  the  posterior 
column  are  here  merely  briefly  indicated.  These  symptoms  are  for  the 
most  part  brought  into  a  relation  of  cause  and  effect  with  the  constant 
hyperglycemia,  yet  this  explanation  is  for  very  many  of  the  cases  as  yet  very 
uncertain.  This  is  also  true  for  the  premature  arteriosclerosis  of  the  dia- 
betic with  its  sequel,  diabetic  gangrene,  which  is  perhaps  the  result  of  the 
hypertonic  condition  we  have  described. 

Let  us  survey  now  the  alterations  of  the  metabolism  in  genuine  diabetes! 
First,  I  would  again  point  out  that  according  to  investigations  up  to  the 
present  there  are  demonstrable  neither  an  increase  of  the  protein  decom- 
position nor  an  increase  of  heat  production.  Why  then  does  a  severe  case 
of  diabetes  become  thin?  The  basis  lies  apparently  in  the  devaluation  of  his 
diet  through  the  limitation  of  sugar  and  of  ketone-bodies.  This  is  especially 
true  of  the  omnivorous,  irrationally  fed,  severe  diabetic.  Such  a  person  loses 
flesh  in  spite  of  the  abundant  ingestion  of  the  food  because  a  certain  part 
of  the  material  ingested  leaves  the  body  unused.  In  such  an  individual  the 
heat  production  can  be  raised  at  most  by  the  increased  work  of  digestion, 
and  because  he  must  warm  the  large  amounts  of  fluids  of  which  he  partakes 
to  body  temperature.  The  polyuria  conditions  a  slight  loss  of  heat.  This 
is  however  an  ectogenous  raising  of  the  heat  production.  In  the  light  and  the 
moderately  severe  diabetic,  he  who  can  be  made  sugar-free  very  early  by  a 
relatively  slight  restriction  of  the  ingestion  of  protein  and  carbohydrate 
and  thus  again  uses  his  diet  to  its  full  value,  there  lies  no  basis  for  emaciation. 
The  severe  diabetic  can  only  be  made  sugar-free  through  great  limitation  of 


GEXUIXE    DIABETES    MELLITUS  545 

the  proteids  and  carbohydrates.  Also  this  individual  may.  as  Weintraud 
has  already  shown,  be  maintained  at  body  weight  for  a  long  time,  on  this 
just  adequate  diet,  indeed  it  seems  as  though  through  the  chronic  under- 
feeding he  may  become  estabhshed  on  a  lower  requirement  for  calories,  as 
we  can  observe  also  in  chronically  underfed  nondiabetic  individuals.  In 
still  further  advanced  stages  of  the  disease,  the  adequate  diet  does  not  serve 
any  longer  to  maintain  freedom  from  sugar  in  the  urine;  indeed  in  very  severe 
cases  it  is  no  longer  possible  to  limit  the  glycosuria  to  a  low  figure,  as  now 
on  account  of  the  strong  formation  of  ketone  bodies,  carbohydrates  must  be 
administered  unconditionally.  That  in  such  cases  the  carbohydrates  are 
in  a  position  to  limit  the  formation  of  ketone  bodies,  at  least  to  some  degree, 
indicates  that  a  part  of  the  carbohydrates  goes  over  the  glycogen  stage, 
although  on  account  of  the  rapid  re-combination  this  cannot  be  demon- 
strated with  certainty  in  respiration  experiments.  The  most  marked  effects 
are  in  such  cases  produced  by  the  exclusive  administration  of  carbohydrates, 
especially  of  oat-meal  {v.  Noorden),  perhaps  because  other  simultaneous 
administration  of  protein  favors  the  re-combination  of  the  formed  glycogen. 
In  such  cases,  too.  we  then  see  the  body  weight  rapidly  increase,  a  phenom- 
enon that  is  certainly  not  explained  by  the  inhibition  of  water  alone.  In 
the  very  highly  advanced  cases  these  carbohydrate  treatments  are,  as  is 
known,  also  of  no  use.  The  severe  diabetic  loses  weight  and  uses  up 
his  protein  constituent,  because  he  can  be  maintained  sugar-free  and 
ketone-body-free  only  on  an  extremely  just  adequate  diet;  as  soon,  how- 
ever, as  the  diet  becomes  more  abundant,  the  ehmination  of  sugar  and  ketone 
bodies  is  increased,  by  which  the  value  of  the  diet  is  detracted  from.  That 
the  fattening  of  severe  diabetics  presents  great  difliculties  is  intelligible  as  it 
is  known  that  a  fattening  is  only  possible  when  abundant  assimilation  of 
carbohydrates  goes  on  at  the  same  time. 

To  me  it  seems  that  very  much  seems  to  speak  for  the  fact  that  the 
metabolic  disturbance  that  is  present  in  genuine  diabetes  mellitus  is  made 
up  of  two  different  factors.  The  one  factor  consists  of  a  disturbance  in 
anaholism.  This  disturbance  in  the  building  up  of  glycogen  is  usually  first 
to  appear.  The  alimentary  influence  is  here  predominant.  In  the  initial 
stages  a  disturbance  becomes  manifest  only  on  overstraining  of  the  carbo- 
hydrate assimilation.  If  we  adopt  the  viewpoint  that  the  disturbance  of 
glycogenesis  affects  both  liver  and  muscle  and  that  combustion  of  the  carbo- 
hydrates in  the  muscles  is  only  possible  after  preceding  assimilation,  we  may 
in  this  sense  speak  also  of  a  disturbance  in  sugar-combustion.  On  account 
of  the  lessened  formation  of  glycogen,  there  gradually  develops  a  deficient 
splitting  up  of  protein  and  fat,  and  the  formation  of  ketone  bodies. 

The  other  factor  consists  in  a  disturbance  of  catahoHsm.  This  is  most 
evident,  when  in  spite  of  the  ruling  out  of  ahmentary  influences  sugar  is 
continually  formed  from  albuminous  and  fatty  substances  and  eHminated 
2>s 


546  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

(increased  sugar-production).  This  increase  of  the  catabolism  must  there- 
fore be  regarded  as  endogenous;  it  leads,  if  the  lack  cannot  longer  be  made 
up  through  ingestion  of  food,  to  a  melting  down  of  albuminous  and  fatty 
substance.  We  can  therefore  very  well  speak  of  an  increased  exchange  in 
severe  diabetics,  whether  this  is  due  to  the  devaluation  of  the  food  adminis- 
tered in  excess,  or  to  a  melting  down  of  the  body  substance.  This  increased 
transformation  is  expressed  in  the  experiments  on  respiration  only  by  increased 
oxvgen  requirements  not  by  increased  carbonic  acid  production  or  heat  production. 

These  two  disturbances  show  a  certain  independence  of  each  other;  in 
the  initial  stages  of  diabetes  the  disturbance  in  anabolism  tends  to  come  to 
the  front,  as  the  predominance  of  the  ahmentary  factor  would  indicate. 
There  do,  however,  exist  cases  in  which  the  catabolic  factor  predominates 
already  at  the  commencement  (neurogenic  diabetes).  In  the  later  stages 
both  factors  are  present  at  the  same  time,  although  they  are  not  always  just 
as  strong  as  each  other. 

If  we  review  once  more  the  alterations  of  metabolism  that  characterize 
the  diabetes  after  extirpation  of  the  pancreas,  and  compare  these  with  those 
of  genuine  human  diabetes,  it  is  not  hard  to  recognize  a  distinct  difference; 
to  both  are  common  the  anabohc  as  well  as  the  catabohc  disturbances.  They 
differ  from  each  other,  however,  in  the  behavior  of  the  protein  exchange  and 
the  heat  production.  In  the  dog  with  pancreatic  diabetes  the  decomposition 
of  protein  and  the  heat-production  are  much  increased;  in  genuine  diabetes 
these  are  not  essentially  altered.  Before  we  discuss  this  fundamental  dif- 
ference, I  must  first  tell  about  the  results  of  pathologico-anatomical  research 
in  genuine  diabetes. 

Pathological  Anatomy  of  Diabetes  Mellitus 

Bouchardat  first  in  1845  expressed  the  opinion  that  diabetes  came  about 
through  a  disease  of  the  pancreas,  at  all  events  Bouchardat  was  forced  to  the 
assumption  that  under  circumstances  only  a  functional  disturbance  may 
exist,  as  in  many  cases  of  diabetes  mellitus  he  found  the  pancreas  normal. 

After  Bouchardat,  Lapirre,  Frerchs,  Cantani.  Scegan,  and  Lanceraux 
drew  attention  to  the  pancreas  in  autopsies  on  diabetics,  and  found  that 
in  addition  to  cases  with  the  most  varied  alterations  of  the  pancreas  there 
were  also  cases  of  diabete  maigre  in  which  the  pancreas  was  apparently 
normal.  In  1891  Lemoine  and  Launois  described  the  sclerosis  of  the  blood 
and  lymph  vessels  in  diabetes.  In  1893  Laguesse  first  expressed  the  view 
that  in  diabetes  the  islands  oi  Langerhans  were  diseased.  In  1894  v.  Hanse- 
mann  described  a  specific  atrophy  of  the  glandular  parenchyma  in  diabetes 
mellitus,  associated  with  proliferation  of  the  connective  tissue  about  the 
acini,  which,  on  account  of  the  similarity  to  granular  atrophy  of  the  kidney 
he  designated  granular  atrophy  of  the  pancreas.     In  a  later  work  v.  Hanse- 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  547 

mann  reported  on  investigations  in  thirty-four  cases  of  diabetes  mellitus. 
In  the  majority  of  these  this  granular  atrophy  was  found,  in  six  cases  was 
found  hyahne  degeneration  of  numerous  islands,  to  which,  however  v.  Hanse- 
mann  attributed  no  great  significance.  Dieckhof  examined  the  islands  espe- 
cially and  among  seven  cases  found  three  times  diminution  in  the  number  of 
islands,  once  disappearance  of  the  islands,  once  the  insular  tissue  qualita- 
tively altered,  and  twice  no  alterations.  He  also  found  that  the  glandular 
parenchyma  for  the  most  part  showed  changes.  In  1898  Schlesinger  first 
reported  that  he  found  in  cases  of  pancreatic  disease  without  diabetes  that 
the  islands  were  remarkably  well  preserved.  In  several  interesting  studies, 
Opie  advocated  the  opinion  that  the  disease  of  the  islands  of  Langerhans 
was  the  cause  of  the  diabetes. 

Opie  distinguished  two  types  of  chronic  inflammation  of  the  pancreas; 
an  interlobar  pancreatitis  (twenty-one  cases)  brought  about  by  occlusion 
of  the  excretory  duct  by  pancreatic  stone  or  gall-stone,  or  by  compression 
of  the  duct  by  tumors,  or  as  the  result  of  an  acute  inflammation  of  the 
pancreas  on  account  of  infection  of  it  from  the  intestine,  or  by  generalized 
tuberculosis,  or  as  an  accompaniment  of  atrophic  cirrhosis  of  the  liver.  Here 
the  islands  are  only  a  httle  altered,  and  indeed  only  altered  if  the  cirrhosis  is 
of  a  very  high  degree.  On  the  contrary  we  find  in  interacinous  pancreatitis 
the  islands  markedly  affected  and  on  marked  changes  in  these  also,  for  the  most 
part,  diabetes.  Opie  describes  among  the  cases  here  observed  also  one  of 
generahzed  hyahne  degeneration  of  the  islands  of  Langerhans.  Ssoholew,  into 
a  consideration  of  whose  experimental  studies  I  have  already  entered,  de- 
scribed alterations  of  the  pancreas  without  diabetes  in  which  the  glandular 
parenchyma  was  in  part  highly  altered,  while  the  islands  seemed  to  be  very 
much  more  resistant.  In  primary  or  metastatic  carcinoma  of  the  pancreas 
the  islands  are  often  retained  in  the  midst  of  the  tumor  tissue;  only  in  one 
case  of  primary  tuberculosis  of  the  pancreas  were  traces  of  sugar  present, 
there  being  present  in  this  case  also  an  extensive  dense  formation.  In 
sixteen  cases  of  diabetes  he  found,  on  the  contrary,  mostly  disappearance 
of  the  islands  or  diminution  of  their  numbers,  or  signs  of  degeneration.  He 
comes  to  the  conclusion  that  in  diabetes,  the  islands  seem  to  be  the  least  resist- 
ant. As  enemies  of  the  insular  theory  appeared  Gutmann,  KarakascJief, 
Herxheimer,  and  others.  Herxheimer  found  in  a  majority  of  these  cases  v. 
Hansemann's  granular  atrophy,  and  in  addition  in  five  cases  found  changes 
with  the  strong  predominance  of  the  regenerative  new  formation  of  excretory 
ducts,  and  he  designates  this  form  cirrhosis  of  the  pancreas  on  account  of  its 
similarity  to  cirrhosis  of  the  liver.  He  did  not  regard  as  significant  the 
changes  he  found  in  the  islands.  Also  Schmidt  maintains  a  sceptical  atti- 
tude. These  authors  show  that  in  diabetes  meUitus  also  the  glandular  paren- 
chyma may  be  very  much  diseased,  and  that  the  islands  throughout  do  not 
have  to  be  the  only  part  diseased;  in  many  cases  the  islands  are  remarkably 


548  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 

well  preserved  or  show  distinct  signs  of  regeneration;  and  in  many  cases 
they  appear  entirely  normal.  Karakaschef  upholds,  as  already  mentioned 
previously,  the  opinion  that  the  islands  constitute  only  reserve  material, 
and  under  circumstances  can  form  new  glandular  parenchyma,  while 
Giitmann  assumes  a  new  formation  of  islands  from  glandular  parenchyma. 
MacCallum  describes  a  case  of  juvenile  diabetes  in  a  child,  in  which  the 
islands  showed,  a  high-grade  hypertrophy.  Before  the  appearance  of  a 
part  of  the  work  directed  against  the  insular  theory,  Sauerbeck  h^d  treated  the 
subject  in  a  "Referat"  [collection  of  references]  and  in  a  monograph.  He 
collected  one  hundred  and  fifty-seven  of  diabetes  from  the  hterature.  The 
islands  found  normal  in  40  per  cent,  of  which  there  were  twenty-six  cases 
with  alterations  of  the  glandular  parenchyma.  Changes  in  the  islands 
were  noted  in  one  hundred  and  seventeen  cases.  In  these  the  islands  were 
not  found  at  all,  or  only  scars  marked  their  places  in  seven.  In  twelve  more 
cases  the  number  of  the  islands  was  diminished  whereby  the  glandular  par- 
enchyma was  rendered  in  part  atrophic.  In  ninety-eight  cases  the  islands 
were  altered  quahtatively,  there  occurring  hemorrhages,  simple  atrophy, 
hyaline  or  fatty  or  hydropic  degeneration,  sclerosis,  or  acute  or  chronic  in- 
flammatory alterations.  In  seventeen  of  his  own  cases  of  diabetes  meUitus 
Sauerbeck  found  mostly  that  alterations  of  the  glandular  parenchyma  ran 
parallel  with  those  of  the  islands,  and  usually  that  in  severe  cases  of 
diabetes  mellitus  distinct  alterations  of  the  islands  were  present.  Sauerbeck 
inclines  more  to  the  insular  theory;  he  believes  that  diabetes  cannot  originate 
from  the  parenchyma,  as  in  cases  of  severe  alterations  of  the  parenchyma 
the  diabetes  may  remain  absent  entirely. 

Recent  times  have  brought  a  series  of  important  studies  on  this  subject. 
V.  Halasz  investigated  twenty-nine  cases  of  diabetes  mellitus.  He  found 
90-95  per  cent,  of  the  islands  normal  eight  times;  six  times  in  60-90  per  cent, 
of  the  islands,  seven  times  in  30-40  per  cent,  of  the  islands,  he  found  al- 
terations that  consisted  in  hemorrhages,  sclerosis,  atrophy,  hyaline  degen- 
eration and  in  atheroma  of  the  blood-vessels.  Signs  of  regeneration  were 
found  only  twice.  Alteration  of  the  parenchyma  was  found  by  Halasz  chiefly 
in  old  diabetics,  and  the  weight  of  the  pancreas  was  for  the  most  diminished, 
often  distinctly,  v.  Halasz  comes  to  the  conclusion  that  not  every  diabetes 
is  a  pancreatic  diabetes.  Heiberg  investigated  six  cases  of  diabetes  mellitus 
and  found  the  islands  either  qualitatively  altered  or  the  number  of  them 
diminished.  Heiberg  attributes  this  defect  in  the  islands  to  their  destruction 
by  inflammatory  processes,  in  which  residues  of  the  inflammation  were  not 
always  necessarily  present.  In  one  case  the  islands  showed  in  part  the  round- 
cell  infiltration  described  by  M.  B.  Schmidt,  Halasz,  and  Cecil  Russell. 
There  was  found  in  addition  in  this  case  islands  with  necrotic  cells,  without 
[round  cell]  infiltration;  Heiberg  regards  these  alterations  as  the  later  stage 
of  the  inflammatory  processes. 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  549 

In  a  later  publication  in  which  Heiberg  reports  on  investigations  of  the 
pancreases  of  two  diabetic  children,  he  again  mentions  that  the  number  of 
the  islands  must  be  considered  as  well  as  their  quahty.  Saltykow  examined 
twenty-one  cases  with  pathologically  altered  pancreas  without  diabetes; 
of  these  four  cases  show  insignificant  alterations  in  the  islands,  which  were 
otherwise  well  preserved.  In  many  cases,  especially  in  sclerosis  and  diffuse 
carcinomatous  infiltration  of  the  pancreas,  the  islands  were  indeed  very  well 
preserved.  In  nine  cases  of  diabetes  Saltykow  found  always  alterations  in 
the  islands.  Among  these  was  a  case  of  isolated  hyaline  degeneration  of 
the  insular  apparatus  with  diabetes,  as  it  had  already  been  described  by 
Opie,  Wright  and  Joslin,  and  others. 

A  far-reaching  confirmation  of  Opie's  findings  was  contributed  by  Russel 
L.  Cecil;  he  found  among  ninety  cases  of  diabetes  alterations  of  the  pancreas 
in  seven,  and  among  these  regularly  alterations  of  the  islands,  such  as 
sclerosis,  hyaline  degeneration,  leucocytic  infiltration.  In  seventy-six  cases 
were  found  fibrosis,  in  twenty-seven  hyaline  degeneration,  etc.  In  twelve 
cases  the  alterations  affected  the  islands  exclusively;  and  among  the  cases 
without  qualitative  alteration  of  the  pancreas  was  found  striking  smallness 
of  the  organs  or  decreased  number  of  islands. 

The  question  has  been  studied  the  most  thoroughly  by  Weichselhaum. 
Weichselhaum  had  previously  reported  with  Stangl  thirty-three  cases  of 
diabetes  mellitus  in  which  striking  alterations  in  the  islands,  but  not  essen- 
tial changes  in  the  parenchyma  had  been  found.  The  latest  communication 
of  Weichselhaum  is  based  on  the  whole  on  one  hundred  and  eighty-three 
cases  of  diabetes  mellitus.  The  number  of  control  experiments  and  pan- 
creases of  nondiabetics  is  still  greater.  Microscopically  the  pancreases  of 
diabetics  often  showed  distinct  atrophy  and  decrease  in  size,  and  fatty 
degeneration;  often  they  were  entirely  normal.  Microscopically  constant 
alterations  in  the  islands  were  found.  In  addition  to  diminution  in  the 
number  of  islands  and  decrease  of  their  extent  {Neumann),  Weichselhaum 
described  a  hydropic  degeneration  of  the  island  cells;  in  this  the  protoplasm 
of  the  cells  loses  its  structure,  becomes  transparent,  shows  characteristic 
granular  inclusions  and  eventually  are  decreased  in  size  (transition  into 
atrophy).  This  hydropic  degeneration  was  found  in  53  per  cent,  of  the 
cases  and  indeed  almost  exclusively  in  younger  individuals.  In  43  per  cent, 
of  the  cases,  mostly  in  persons  over  fifty  years  of  age,  Weichselhaum  found 
sclerosis  of  the  islands,  proliferation  of  the  connective  tissue  in  and  about 
the  islands,  and  mostly  interlobar  and  intralobar  proliferation.  There  was 
found  also  sclerosis  of  the  arteries.  In  28  per  cent,  of  the  cases  there  was 
found  hyaline  degeneration  of  the  island  cells  together  with  the  sclerosis 
above  mentioned.  Manifestations  of  regeneration  of  the  islands  were 
found  chiefly  in  the  head  of  the  pancreas,  and  indeed  in  young  individuals. 
Hypertrophy  of  the  islands  were  found  only  in  some  cases  of  insular  sclerosis. 


550  DISEASES    OF    THE    IXSULAR    APPARATUS    OF    THE    PAN'CREAS 

While  therefore  the  insular  apparatus  regularly  showed  alterations,  high- 
grade  degeneration  of  the  glandular  parenchyma  was  found  only  in  closure 
of  the  pancreatic  duct  or  in  carcinoma  of  the  pancreas.  In  the  control 
investigations  on  the  pancreases  of  non-diabetic  individuals  these  changes 
were  almost  always  absent,  but  on  the  contrary  there  existed  high-grade 
atrophy  of  the  glandular  parenchyma,  whereby  the  weight  of  the  pancreas 
was  very  much  diminished;  in  chronic  tuberculosis  even  to  20  gm.  Weich- 
selhaiim  mentions  that  in  diabetes  mellitus  the  relation  between  regeneration 
and  destruction  of  the  islands  must  be  considered;  and  not  only  the  structure 
but  also  the  number  of  islands. 

On  the  basis  of  his  investigations  Weichsclhaum  distinguished  from  the 
pathologico-anatomical  standpoint  three  forms  of  human  diabetes;  first  a 
youthful  form,  the  proper  diabete  maigre,  in  which  is  found  the  hydropic 
degeneration  of  the  islands;  this  is  hereditary  and  would  seem  to  depend 
on  congenital  weakness  or  on  failure  of  formation  of  the  insular  apparatus. 
Then  he  distinguished  the  form  dependent  on  chronic  interstitial  pancreatitis, 
that  occurs  in  the  later  years  of  life  and  is  commonly  associated  with  lipoma- 
tosis of  the  pancreas  and  general  adiposis  (diabete  gras).  This  form  is  hence 
lipogenous  or  depends  on  a  chronic  catarrh  of  the  excretory  ducts  and  chronic 
alcoholism  and  is  often  complicated  with  cirrhosis  of  the  liver.  Finally 
the  third  form,  which,  depending  on  the  hyahne  degeneration  of  the  islands, 
occurs  in  the  later  years  of  life,  apparently  is  a  subvariety  of  the  second 
form,  and  is  usually  associated  with  sclerosis  of  the  arteries. 

I  have  reproduced  rather  in  detail  the  numerous  labors  as  to  the  patho- 
logical anatomy  of  the  pancreas  in  "genuine  diabetes,"  and  have  purposely 
confined  myself  strictly  to  the  words  of  the  various  authors,  because  it  seemed 
to  me  that  an  intimate  penetration  into  the  development  of  the  question 
makes  its  solution  essentially  easier.  On  reviewing  once  again  the  entire 
material  detailed,  we  see  that  with  increasing  exactness  the  microscopical 
investigation  and  also  the  findings  of  the  pathologico-anatomical  alterations 
in  the  islands  have  become  essentially  commoner,  so  that  the  later  authors 
almost  all  belong  to  the  adherents  of  the  insular  theory.  It  is  further  per- 
fectly clear  that  pathologico-anatomical  alterations  found  in  so-called  genuine 
diabetes  melhtus  are  not  of  a  uniform  nature,  a  conception  that  is  upheld 
in  the  larger  and  more  thorough  of  the  works  cited.  A  large  group  possesses 
well-defined  characteristics,  although  the  names  given  to  it  by  dift'erent 
authors  are  dift'erent.  It  is  the  form  of  interacinous  pancreatitis  occurring 
in  later  life,  that  v.  Hansemann  calls  granular  atrophy  of  the  pancreas,  Opic, 
interacinous  sclerosis.  Lepiiie,  and  Lcmoine  and  Lauiiois,  sclerose  periacineuse, 
and  which  Weichsclhaum  regards  as  dependent  on  interstitial  pancreatitis. 
The  causes  of  it  are  probably  very  dift'erent.  In  part  they  are  sclerotic 
changes  similar  to  those  of  cirrhosis  of  the  liver,  often  occurring  in  common 
with  hepatic  cirrhosis  and  like  it  dependent  on  alcoholism.     Commonly 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  551 

the  cause  can  be  ascribed  to  high-grade  arteriosclerosis  of  the  vessels  of 
the  pancreas;  in  other  cases  an  ascending  catarrh  of  the  duct  system  might 
be  the  cause.  The  latter  cases  go  over  without  sharp  boundary  into  that 
large  group  of  high-grade  atrophies  of  the  pancreas,  which  we  previously 
treated  under  the  gross  anatomical  alterations  of  the  pancreas.  In  all 
these  cases  are  found  in  addition  to  changes  in  the  insular  apparatus  more  or 
less  pronounced  alterations  of  the  glandular  acini,  which  is  true  of  the  cases 
that  proceed  from  catarrhs  of  the  excretory  ducts  only  when  the  process  is 
more  advanced.  It  is  comprehensible  why  these  cases  do  not  lead  to  absorp- 
tive disturbances,  for  there  is  still  enough  functionating  parenchyma  present, 
and  it  is  to  be  expected  that  such  disturbances  became  manifest  only  on  high- 
grade  diminution  of  pancreatic  juice  production.  The  decision  as  to  whether 
the  alterations  in  the  insular  apparatus  observed  in  this  form  suffice  to  explain 
the  disturbance  in  carbohydrate  metabolism  is  certainly  very  difficult,  and 
is  further  complicated  by  the  occurrence,  commonly  observed,  of  regenera- 
tive manifestations  in  the  islands.  It  is  indeed  very  questionable  whether 
these  new-formed  islands  have  the  same  functional  integrity.  We  see,  how- 
ever, in  many  forms  of  cirrhosis  of  the  liver  often  strongly  developed  and  wide- 
spread regeneration  of  the  liver  tissue,  and  yet  we  find  in  these  cases  signs 
of  Jdeficiency  of  liver  function.  Also  the  occurrence  of  individual  hyper- 
trophic islands  and  adenomatous  proliferations  of  islands  does  not  furnish  a 
certain  conclusion  as  to  the  function  of  the  entire  insular  apparatus.  Like- 
wise, as  Saltykow  points  out,  just  as  little  does  the  finding  of  partially  normal 
islands  speak  against  the  island  theory;  for  example,  we  have  in  cases 
of  nephritis,  large  amounts  of  normal  renal  parenchyma  visible  micro- 
scopically, without  casting  doubt  as  to  the  insufficiency  of  the  renal  tissue. 
That  also  in  this  group  are  found  cases  in  which  the  insular  apparatus  has 
suffered  relatively  severe  damage  need  cause  no  wonderment.  Weichselhaum 
emphasizes  the  fact  that  the  cases  with  isolated  hyaline  sclerosis  of  the  insular 
apparatus  probably  form  only  a  subdivision  of  this  group;  also  here  is 
commonly  found  a  sclerosis  of  the  vessels  of  the  organ;  it  seems  to  me  very 
likely,  however,  that  in  these  cases  of  isolated  sclerosis  of  the  insular  ap- 
paratus there  is  expressed  a  certain  undervaluation  in  the  rudiments  of  the 
insular  apparatus,  that  becomes  manifest  only  on  the  additional  occurrence  of 
further  damaging  influences. 

For  the  judgment  of  the  role  that  the  pancreas  plays  in  the  pathogenesis 
of  diabetes  mellitus,  no  doubt  the  second  group — that  which  affects  youthful 
individuals — is  the  more  significant.  Most  important  for  us  are  those  cases 
in  which  the  diabetes  commences  at  an  early  age,  and,  ceaselessly  progressing, 
leads  to  fatal  coma.  It  is  these  cases  that  up  to  the  present  have  furnished  so 
unsatisfactory  pathologico-anatomical  findings.  The  monographs  on  dia- 
betes by  Naimyn  and  by  von  Noorden  state  likewise  that  in  the  rich  experi- 
ence of  these  authors  numerous  cases  are  met  with,  in  which  even  the  most 


552  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

careful  microscopical  examination  of  the  pathological  anatomists  did  not  show 
anything  certain.  In  one  of  these  cases  the  count  of  the  islands  has  furnished 
inferences  worthy  of  remark.  It  is  shown  in  this  group  that  the  number  of 
islands  and  also  their  size  is  markedly  diminished,  and  indeed  there  are 
statements  that  the  islands  are  entirely  wanting.  The  supposition  of 
Heiherg  that  in  such  cases  the  defect  in  islands  can  be  referred  to  a  preceding 
inflammation  with  the  formation  of  scars  has  much  in  its  favor.  In  many 
cases  of  juvenile  severe  diabetes,  however,  the  number  and  size  of  the  islands 
is  insignificantly  and  perhaps  not  even  at  all  diminished.  In  these  cases 
Weichselbaum  constantly  found  the  hydropic  degeneration.  This  statement 
of  Weichselbaum  s  has  up  to  the  present  time  not  been  recognized  by  all 
pathological  anatomists.  If,  however,  the  hydropic  degeneration  in  such 
cases  is  found  to  be  constant,  we  must  also  ask  the  question  if  the  alterations 
are  not  of  a  secondary  nature,  brought  into  existence  by  the  long  duration 
of  the  hyperglycemia  and  acidosis,  and  if  these  relatively  slight  alterations 
suffice  to  explain  the  high-grade  functional  deficiency.  This  form  of  diabetes 
always  commences  with  heavy  elimination  of  sugar.  In  the  majority  of 
cases  there  is  found  in  the  later  stages  an  intensity  of  glycosuria,  that  comes 
up  to  that  seen  in  pancreasless  dogs,  and  in  the  most  of  cases  even  exceeds 
this.  On  the  whole  we  can  hardly  be  mistaken  if  we  were  always  to  assume  a 
participation  of  the  pancreas  in  such  cases.  The  hereditary  element  so 
conspicuous  in  the  pathology  of  this  form  of  diabetes  points  to  a  weakness 
in  the  "Anlage"  of  the  insular  apparatus,  as  a  result  of  which  any  toxic  or 
infectious  deleterious  influence  at  all  finds  a  locus  resistentiae  minoris.  In 
spite  of  all  this  we  cannot  reconcile  the  incongruity  of  the  pathologico- 
anatomical  findings  and  the  intensity  of  the  metabolic  disturbance  and  must 
ask  ourselves  the  question  whether  if  in  this  form  of  human  diabetes,  and 
perhaps  in  the  most  cases  of  severe  human  diabetes,  there  is  not  present,  in 
addition  to  the  insufficiency  of  the  pancreas,  also  another  disturbance  that 
we  have  essentially  to  regard  as  an  increase  of  sugar  production  dependent  on 
a  nervous  basis. 

Before  we  enter  into  this  question,  it  is  necessary  to  observe  more  care- 
fully those  forms  of  diabetes  in  which  the  clinical  observation  or  the  patho- 
logical anatomy  points  toward  a  prominent  participation  of  the  nervous 
system  in  the  coming  about  of  the  diabetic  disturbance  of  metabolism. 

The  question  as  to  whether  we  are  justified  in  recognizing  a  "nervous 
form"  of  diabetes  has  been  discussed  in  a  lively  manner  for  a  long  time. 
The  discovery  of  the  "piqure"  happened  before  that  of  diabetes  after  extir- 
pation of  the  pancreas.  Since  the  time  that  the  discovery  of  pancreatic 
diabetes  turned  the  general  attention  toward  the  pancreas,  the  interest  in 
nervous  diabetes  has  fallen  behind.  The  greater  part  of  the  clinical  observa- 
tions of  ''nervous"  diabetes  come  from  earlier  times,  thus  making  critical 
observations  not  less  difficult. 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  553 

I  shall  first  select  from  the  observations  at  hand  those  which  seem  to  me 
the  most  important,  and  describe  them  more  exactly. 

Glycosuria  occurs  not  infrequently  in  brain-hemorrhages  and  encephalo- 
malacias.  This  was  first  described  by  Leudet.  They  may  be  associated  with 
acute  hemorrhages  as  well  as  the  chronic  encephalomalacias.  A  case  of  the 
latter  sort  is  described  by  Naunyn  in  which  the  diabetes  gradually  developed 
during  a  slowly  progressing  encephalomalacia.  For  the  most  part  there 
exists  in  addition  to  the  glycosuria,  polyuria,  and  also  even  albuminuria. 
Cases  of  the  first  kind  are  communicated  by  Dutrait,  Frerichs,  and  others. 
The  seat  of  the  hemorrhage  or  softening  in  such  cases  associated  with 
glycosuria  is  mostly  the  pons  or  its  vicinity.  Especially  interesting  is  the 
case  of  Reinhold.  In  a  sixty-three  and  one-half-year-old  woman  with 
melancholia,  ten  days  before  death  there  developed  a  marked  edema  of  the 
feet  and  strong  glycosuria.  Section  showed  a  hemorrhage  on  the  floor  of 
the  fourth  ventricle  (serial  sections),  slight  hydrocephalus,  and  a  strong 
hyperemia  of  the  liver.  It  should  not  remain  unmentioned  that  glycosuria 
is  sometimes  observed  in  the  parts  of  the  brain  that  lie  further  off,  and  that 
cases  occur  in  which  there  is  no  glycosuria  in  spite  of  hemorrhages  in  the 
neighborhood  of  the  pons.  Such  a  case  is  reported  by  Lemcke.  In  this 
case  there  was  an  enormous  lowering  of  the  body  temperature  to  23°C. 
There  was  found  neither  glycosuria  nor  albuminuria.  Section  showed  a 
fresh  focus  of  hemorrhage  beneath  the  floor  of  the  fourth  ventricle. 

It  is  an  interesting  fact  that  H.  Strauss  in  tests  for  alimentary  glycosuria 
in  cases  with  fresh  apoplectic  attack,  several  times  found  them  positive  im- 
mediately after  the  attacks  but  they  were  negative  later.  In  this  category 
belong  too  the  cases  of  brain  hemorrhage  after  trauma  to  the  head.  The 
first  case  was  described  by  Claude  Bernard  (Physiol,  experim.,  Tom.  i, 
1855).     Glycosuria  disappears  at  the  same  time  as  does  the  wound. 

Here  also  belongs  the  case  of  Drummond.  A  seventy-six-year-old  man 
suffered  a  blow  on  the  head.  Since  that  time  increasing  weakness,  thirst, 
and  glycosuria.  Autopsy  showed  besides  an  extreme  dilatation  of  the 
lateral  ventricle  and  the  aqueduct  of  Sylvius,  a  small  blood  effusion  in  the 
fourth  ventricle. 

I  mention  further  the  case  of  Kdmmitz.  A  seventeen-year-old  girl,  pre- 
viously well,  caught  her  head  in  a  cutting  machine.  Loss  of  consciousness, 
later  vomiting,  and  copious  bleeding  from  the  nose,  and  downflow  of  blood 
along  the  posterior  wall  of  the  pharynx  pointed  with  certainty  to  fracture 
of  the  base  of  the  skull.  The  temperature  at  first  was  35°C.  After  two  days 
an  abducens  paralysis  became  evident.  A  week  after  the  trauma  there  de- 
veloped increased  thirst,  polyuria,  and  glycosuria  (about  i  per  cent,  sugar). 
The  sugar-contents  gradually  rose  to  2.3  per  cent.  There  now  existed  excess- 
ive polyuria.  About  three  weeks  after  the  trauma  the  somnolent  condition 
had  disappeared,  the  diplopia  still  existed,  and  a  unilateral  hypoglossus 


554  DISEASES    OF    THE    INSULAR    APPAR.\TUS    OF    THE    PAN'CREAS 

paralysis  had  developed.  During  the  next  few  weeks,  the  sugar  following 
exclusive  meat  diet  fell  to  i  per  cent.,  but  the  polyuria  had  decreased  but 
little.  Two  months  after  the  trauma  traces  of  sugar  were  still  present,  one 
month  later  the  urine  in  spite  of  abundant  ingestion  of  food  was  entirely 
free  of  sugar,  but  there  still  existed  a  diuresis  of  4-6  liters,  with  a  specific 
gravity  of  1005.  Nothing  was  noted,  unfortunately,  as  to  the  further 
course.  The  supposition  of  a  hemorrhage  in  the  medulla  oblongata,  that 
became  still  more  marked  some  time  after  the  trauma,  is  very  probable  in 
this  case. 

Entirely  similar  is  the  case  of  Plagge.  A  sixteen-year-old  boy  suffered 
a  head  injury,  after  which  amblyopia  and  strong  glycosuria  commenced. 
The  glycosuria  disappeared  after  two  or  three  weeks,  while  the  polyuria 
remained  for  two  or  three  months. 

Further  I  might  still  mention  the  case  of  Loeb.  In  the  first  case  (pontile 
hemorrhage  with  rupture  into  the  fourth  ventricle  and  with  general  arterio- 
sclerosis) sugar  and  albumin  were  found  in  the  urine.  The  urine  had  been 
examined  previously  and  found  to  be  free  of  sugar.  In  the  second  case 
there  occurred  after  an  apoplexy  (probably  small  hemorrhage  of  the  pons) 
sugar  and  albumin  in  the  urine.  All  manifestations  later  vanished  leaving 
not  a  trace  behind.     Loeb  regards  the  albuminuria  as  conditioned  centrally. 

In  addition  to  the  hemorrhages,  it  is  chiefly  tumors  and  abscesses  in  this 
region  that  can  lead  to  glycosuria.  The  case  of  Iwan  Michael  is  much  cited. 
In  a  twenty-five-year-old  man  there  occurred,  together  with  increasing  weak- 
ness and  tormenting  headache,  polyuria,  polydipsia,  and  glycosuria.  The 
amount  of  urine  reached  over  610Q  cubic  centimeters,  the  elimination  of 
sugar  reached  to  25  mg.  Death  in  coma  followed  later.  Autopsy  showed  a 
cysticercus  racemosus  of  the  floor  of  the  fourth  ventricle.  Sleida  reports  on 
the  contrary  a  case  of  cysticercus  racemosus  of  the  fourth  ventricle  which, 
in  spite  of  changes  in  the  floor  of  the  ventricle,  did  not  call  forth  glycosuria. 

Of  the  other  changes  in  the  floor  of  the  fourth  ventricle  associated  with 
glycosuria  have  been  observed  tubercle  (de  Jonge)  sclerosis,  abscesses  and 
tumors  (especially  gliomata).  The  changes  may  also  aflect  the  vicinity  of 
the  cerebellum.  The  first  glioma  was  reported  by  Xevrat-Perrotton;  other 
cases  are  described  by  Reimer,  Catola  and  others.  Especially  worthy  of 
remark  is  the  case  of  van  Ordt.  It  concerned  an  eight-and-one-half-year-old 
girl  in  whom  no  sugar  was  found  at  the  beginning  of  the  illness.  The  test 
for  alimentary  glycosuria  was  first  positive  on  the  aggravation  of  the  tumor 
symptoms,  then  3I2  per  cent,  of  sugar  occurred  in  the  urine,  then  on  limita- 
tion of  the  carbohydrates  in  the  diet  the  sugar  disappeared,  later  to  reap- 
pear also  on  a  strict  diet  to  the  extent  of  }4  per  cent.  The  autopsy,  in  addi- 
tion to  sho^\^ng  several  miliary  tubercles  on  the  floor  of  the  fourth  ventricle, 
revealed  a  tumor  in  the  territory  of  the  posterior  corpora  quadrigemina,  the 
pes  cerebri,  and  the  tegmentum  of  the  pons,  which  also  involved  the  floor  of 


PATHOLOGICAL    ANATOMY    OF    DLABETES    MELLITUS  555 

the  fourth  ventricle.  According  to  the  judgment  of  van  Ordt.  this  could  have 
been  present  only  in  the  course  of  the  last  weeks.  The  pancreas  was  found 
to  be  normal.  According  to  van  Ordt's  statistics,  glycosuria  has  been  found 
up  to  the  present  in 

Cerebral  tumors i  time 

Cerebellar  tumors i  time 

Basal  ganglionic  tumors 

Thalamic  tumors 3  times 

Tumors  of  the  corpora  quadrigemina 3  times 

Dorsal  pontile  tumors 5  times 

Basal  pontile  tumors 

Tumors  of  the  floor  of  the  fourth  ventricle i8  times 

If  we  take  only  those  cases  in  which  the  floor  of  the  fourth  ventricle  was 
destroyed  to  a  greater  or  less  extent,  we  find  that  70  per  cent,  of  all  these 
cases  are  associated  with  glycosuria.  Tests  for  alimentary  glycosuria  were 
found  positive  five  times  in  eleven  cases  of  tumors  of  the  interior  of  the  skull, 
three  times  in  sixteen  cases  of  other  diseases  of  the  brain  (among  them  one 
case  of  lues).  It  should  be  mentioned  that  abscesses  of  the  cerebellum 
very  commonly  lead  to  increase  of  temperature  and  glycosuria  (Hammond'). 

I  believe  that  among  the  cases  detailed  as  well  as  among  numerous 
analogous  cases  there  are  those  which  fulfill  all  the  requisitions  of  a  diabetes 
conditioned  nervously.  It  is  true,  as  Xaunyn  says,  that  he  has  seen  many 
cases  of  apoplexy  with  glycosuria  but  that  he  could  not  exclude  in  these  the 
possibility  that  a  slight  diabetes  did  not  exist  beforehand.  It  must  further 
be  said  that  exact  examinations  of  the  pancreas  especially  with  reference  to 
the  insular  apparatus  are  scarcely  at  hand.  We  can,  however,  only  with 
difficulty  conceive  how  in  individuals  with  pre\'iously  perfectly  normal  sugar- 
metabolism,  and  especially  in  the  youthful  cases,  so  high  grade  a  damage 
to  the  pancreas  can  develop  so  suddenly.  The  parallelism  in  the  develop- 
ment of  the  glycosuria  and  the  brain  symptoms  points  much  the  more  to 
the  fact  that  alterations  in  the  nervous  system  have  a  decisive  significance. 
According  to  the  experimental  experience  up  to  the  present  only  the  assump- 
tion of  an  irritation  of  the  nervous  centers  and  paths  as  cause  of  the  "  nervous' 
glycosuria  is  possible.  It  is  therefore  intelligible  that  pathological  altera- 
tions in  the  neighborhood  of  the  floor  of  the  ventricle  or  the  subthalamic 
region  do  not  always  necessarily  lead  to  glycosuria.  Irritation  would 
the  sooner  follow  if  tumors  or  apoplexies  gradually  encroach  upon  the 
corresponding  centers;  rapid  destruction  of  these  centers  on  account  of  hemor- 
rhage or  softening  would  much  rather  lead  to  symptoms  that  are  the  opposite 
of  irritative  symptoms.  The  case  of  Lemcke  with  considerable  hypothermia 
may  be  perhaps  explained  in  the  above  way.  I  should  like  to  point  out 
one  point  further,  namely,  the  strong  hyperemia  of  the  liver  in  Reinhold's 
case,  which  is  seen  regularly  too  after  the  piqure. 


556  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PAXCREAS 

The  cases  of  diabetes  after  trauma  here  need  a  more  exact  analysis.  We 
have  to  consider  the  following  points: 

1.  WTiether  the  diabetes  began  immediately  or  at  least  a  short  time  after 
the  trauma,  or  after  an  interval  of  several  months  or  years. 

2.  Whether  the  trauma  affected  the  head  and  whether  other  brain  symp- 
toms existed  in  addition  to  the  glycosuria,  or  whether  other  parts  of  the 
body  were  affected  by  the  trauma. 

3.  Whether  the  diabetes  healed  again,  or  whether  it  existed  further  or 
relapsed;  in  short,  whether  a  chronic  diabetes  developed. 

Concerning  the  frequency  of  these  different  factors  several  statistics  are 
at  hand.  Jodry  (cited  by  Lepine)  collected  one  hundred  and  forty-five  cases 
of  diabetes  after  trauma.  The  trauma  affected  the  head  in  seventy-two 
cases — 50  per  cent. ;  the  vertebral  column  in  twenty-seven  cases — 20  per  cent.; 
the  abdomen  in  twelve  cases — 8  per  cent.;  the  seat  of  the  trauma  was  not 
defined  in  1.7  per  cent. 

In  a  third  of  the  cases,  the  diabetes  became  manifest  during  the  first 
days  after  the  trauma. 

Lepine  analyzed  twenty-nine  well  observed  cases  from  the  literature  and 
added  five  cases  of  his  own.  The  symptoms  of  diabetes  appeared  in  the 
first  three  days — ten  times;  in  the  first  week — five  times;  in  the  first  three 
months — twelve  times;  later  seven  times. 

AsJier  found  among  one  hundred  and  twenty-nine  cases  of  diabetes  after 
trauma  fifty-four  cases  of  injuries  of  the  head;  sixty-two  cases  of  injuries 
of  other  parts  of  the  body;  nine  cases  after  injuries  of  an  undefined  kind. 

Higgins  and  Ogden  among  two  hundred  and  twelve  cases  of  head-injury, 
found  sugar  in  9.3  per  cent.  If  only  the  severest  cases  were  considered,  the 
percentage  rose  to  23.4  per  cent. 

Among  eighty-four  cases  of  simple  wound  of  the  scalp,  sugar  was  found 
in  5.95  per  cent. 

Among  forty-three  cases  of  wounds  of  the  scalp  that  laid  bare  [freilegten] 
the  bone,  in  9.3  per  cent. 

Among  forty  cases  of  concussion  of  the  brain  with  loss  of  consciousness, 
but  without  fracture,  in  2.'^  per  cent. 

Among  twenty-four  cases  with  fracture  of  the  vault  of  the  skull,  in  20.8 
per  cent. 

Among  twenty-one  cases  with  fracture  of  the  base  of  the  skull  in  23.8  per 
cent. 

The  question  as  to  the  connection  between  trauma  and  diabetes  has  been 
discussed  in  a  lively  manner.  Ebstein  and  later  Kaiisch  collected  the  cases  of 
traumatic  diabetes  from  the  literature.  WTiile  Ebstein  inclines  to  the  view 
that  also  cases  of  chronic  diabetes,  eventually  diabetes  first  occurring  a  long 
time  after  the  trauma  may  be  ascribed  to  the  trauma,  KauscJi  is  very 
sceptical.     He  would  hold  as  valid  only  the  ephemeral  or  transitory  glyco- 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  557 

surias  occurring  immediately  after,  or  only  a  short  time  after  the  trauma, 
and  denies  the  connection  between  trauma  and  chronic  diabetes,  especially 
when  the  latter  first  occurs  a  long  time  after  [the  accident].  I  believe 
that  we  must  consider  Kausch  right  in  many  points,  even  if  perhaps  he  goes 
too  far,  in  the  separation  of  the  ephemeral  or  transitory  glycosurias  and 
chronic  diabetes.  It  seems  to  me  appropriate  to  go  a  little  further  into  the 
points  [just]  previously  sketched.  I  am  not  regarding  the  responsibility 
serving  for  the  law  for  accidents.  Naunyn  and  v.  Noorden  mention  that  one 
must  not  be  too  narrow-minded,  as  considering  the  obscurity  of  the  condi- 
tions, individuals  should  not  suffer  harm  on  account  of  theoretical  considera- 
tions. The  scientific  side  of  the  question,  however,  demands  a  much  stricter 
criticism. 

Now  as  regards  what  concerns  the  first  point,  we  can  ascribe,  with  con- 
siderable justification,  diabetes  after  head  injury  to  the  injuries  of  the  nervous 
centers  regarding  sugar-metabolism,  when  the  elimination  of  sugar  occurs 
within  the  first  eight  to  fourteen  days  and  especially  when,  too,  other  symptoms 
are  present  that  indicate  an  injury  to  the  brain  stem  and  medulla  oblongata. 
I  have  mentioned  in  brief  several  such  cases  on  page  553.  As  further  examples 
I  would  cite  both  cases  of  Bouchard.  In  a  seventeen-year-old  and  twenty- 
one-year-old  man  respectively  there  occurred,  after  fracture  of  the  base  of  the 
skull  glycosuria  to  1.5  per  cent,  and  1.75  per  cent.,  and  albuminuria  and  cylin- 
druria.  The  first  case  healed  entirely,  but  the  second  case  died  after  some 
days.  If  no  brain  symptoms  are  otherwise  present,  we  cannot,  however, 
deny  without  anything  further  the  connection  with  the  trauma.  Very  in- 
teresting is  the  observation  oiHoniger  that  new-born  infants  whose  heads  have 
been  strongly  squeezed  by  the  artificially  induced  birth,  can  show  glycosuria 
for  several  days,  while  the  long  duration  of  a  spontaneous  birth  never  leads 
in  itself  to  glycosuria. 

If  the  glycosuria  starts  in  a  longer  time  after  the  trauma,  we  can  here  also 
not  deny  the  connection  with  trauma  in  every  case  without  anything  further. 
It  is  conceivable  that  blood  effusions  that  are  undergoing  absorption  in  organi- 
zation, may  exercise  an  irritation  in  the  corresponding  centers  through  shrink- 
age and  the  action  of  traction  {Rosenherger) .  Of  course  this  would  hold  only 
for  very  few  cases.  We  may  regard  that  of  Schaper  as  such  a  one.  In  a  duel, 
a  dagger  thrust  penetrated  the  orbit  and  went  deep  into  the  cranial  cavity. 
There  developed  a  right-sided  paralysis  and  gradually  a  high-grade  diabetes. 
Death  occurred  after  three  and  a  half  months;  it  was  found  that  the  path  of 
the  stab  reached  to  the  left  border  of  the  medulla  oblongata  and  was  filled 
with  pus  and  coagulated  blood.  There  should  finally  still  be  thought  of,  in 
such  cases  of  later  glycosuria,  the  spontaneous  glycosuria  of  the  traumatic 
neurosis.  We  shall  consider  this  latter  in  the  discussion  of  the  connection  of 
psychoses  or  psychic  excitements  with  glycosuria.  The  fact  whether  there 
is  polyuria  is  important  in  the  solution  of  the  question  as  to  whether  the  late 


558  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANXREAS 

glycosuria  is  associated  in  any  way  with  the  trauma.  In  many  cases  of 
head  injury  the  glycosuria  starts  in  simultaneously  with  pronounced  polyuria. 
Usually  both  develop  at  the  same  time.  If  the  glycosuria  later  disappears, 
the  polyuria  often  lasts  for  many  months,  in  other  cases  the  polyuria  develops 
first,  and  the  glycosuria  accompanies  it  only  after  weeks  or  e\'en  months. 
The  centra]  origin  of  such  polyuria  is  very  probable.  On  it  is  based  the  hy- 
pothesis of  a  central  origin  of  the  glycosuria.  In  any  case  the  similarity 
with  the  sugar  and  polyuria  puncture  is  worthy  of  notice. 

The  second  question  concerns  itself  with  whether  glycosurias  after 
trauma  that  does  not  affect  the  head,  but  other  parts  of  the  body,  can  be 
referred  to  the  trauma  and  can  be  regarded  as  nervous  glycosurias.  Kausch 
himself  has  furnished  noteworthy  contributions  to  this  subject.  He  described 
twelve  cases  of  fractures  of  the  pelvis,  thigh,  leg.  patella,  or  toes,  that  showed 
ephemeral  glycosuria.  This  glycosuria  continued  for  at  most  ten  days  and 
under  circumstances,  on  the  ingestion  of  grape-sugar,  would  be  increased  to 
30  gm.  It  is  w^orthy  of  remark  that  these  cases  later  did  not  show  any  alimen- 
tary glycosurias  and  therefore  presented  an  entirely  normal  carbohydrate 
metabolism.  Before  Kausch,  Haedke  has  already  pointed  out  that  after 
traumata  of  ditferent  kinds  alimentary  glycosurias  would  be  obtained  in  a 
large  percentage.  The  connection  of  such  transitory  glycosurias  with  trauma, 
in  cases  that  are  not  narcotized,  is  doubtless.  Experimental  pathology  (gly- 
cosuria after  injury  to  the  sciatic,  etc.)  gives  us  an  idea  as  to  the  kind  of  con- 
nection. Very  much  severer  is  the  significance  in  a  series  of  cases,  of  which  I 
shall  quote  the  following  cases  of  Scheuplein  more  exactly. 

A  young  soldier  who  was  not  hereditarily  predisposed  to  diabetes  fell 
about  12  meters  from  a  third-story  window.  He  fell  on  his  buttocks. 
There  was  found  a  luxation  of  the  first  lumbar  vertebra,  without  there  being 
symptoms  that  pointed  to  an  injury  of  the  spinal  cord.  Reposition  was  suc- 
cessful; complete  cure  resulted,  so  that  later  the  patient  could  again  ride  and 
carry  on  severe  bodily  labor  as  menial  servant  [in  the  army].  Fourteen  days 
after  the  fall  it  occurred  that  the  urine  was  much  thinned  and  pale,  and  that 
the  feeling  of  thirst  was  distinctly  increased.  The  urine  contained  sugar. 
Ten  days  later  the  sugar-content  of  the  urine  was  very  great,  and  the  amount 
of  urine  reached  about  13  liters.  The  patient  was  placed  on  a  meat  diet. 
After  fourteen  days  the  sugar  had  disappeared,  but  the  polyuria  remained 
for  a  while  longer.  Two  years  after  the  trauma  the  patient  was  entirely 
free  of  sugar,  although  his  diet  consisted  chiefly  of  cereals.  The  body  weight, 
that  at  the  time  of  the  sugar  elimination  had  sunk  very  low,  raised  again  so 
that  in  short  the  patient  could  be  regarded  as  cured  in  every  respect.  The 
significance  of  this  case  is  indeed  not  easy  [to  determine].  We  could  perhaps 
think  of  an  apoplexy  of  the  pancreas,  but  against  this  speaks  the  simultaneous 
diabetes  insipidus.  Against  a  hemorrhage  in  the  medulla  oblongata  speaks 
the  absence  of  any  other  brain  symptoms.     Scheuplein  discussed  the  possi- 


PATHOLOGICAL    ANATOMY    OF    DIABETES    MELLITUS  559 

bility  of  an  injury  of  the  solar  ganglion.  To  me  the  possibility  seems  in  any 
case  to  be  thought  of  that  on  account  of  the  great  swelling  formed  by  the 
injured  vertebra  there  followed  an  irritation  of  the  sympathetic  paths  in 
their  course  from  the  sugar  center  to  the  suprarenals.  By  this  means  can 
be  explained  even  the  polyuria.  Scheuplein  also  refers  to  a  case  of  Braun. 
In  a  twelve-year-old  boy  there  existed  a  spondylitis  of  the  twelfth  thoracic 
and  first  lumbar  vertebrae  with  an  acute-angled  kyphosis.  When  the  boy 
was  placed  in  a  horizontal  position,  symptoms  of  collapse,  with  polyuria 
and  glycosuria,  developed.  Comfortable  lying  on  roll  pillows  brought  about 
a  cessation  of  all  manifestations.  Also  I  must  not  leave  unmentioned  the 
case  of  Schwenkendick.  A  man  sustained  a  tread  of  a  foot  in  the  vicinity  of 
the  navel.  After  some  hours  great  thirst  and  polyuria  started.  Two  days 
afterward  there  occurred  stormy  manifestations,  marked  pallor  of  the  face, 
coldness  of  the  extremities,  distention  of  the  abdomen,  frequent  vomiting. 
The  urine  was  at  first  free  of  albumin  and  sugar,  after  two  days  more  there 
was  found  4.75  per  cent,  of  sugar  and  abundant  acetone.  Later  the  patient 
evacuated  black  stools  that  contained  blood,  and  death  soon  followed  under 
manifestations  of  coma.  The  author  thinks  of  apoplexy  of  the  pancreas 
or  necrosis  of  the  pancreas  as  an  affection  of  the  splanchnic  nerves. 

It  is  possible  that  in  the  setting  free  of  this  glycosuria,  pain  plays  a  con- 
siderable role.  For  instance,  it  has  been  known  for  a  long  time  that  in  severe 
neuralgias  there  exists  inclination  to  alimentary  glycosuria.  Frerichs  reports 
such  a  case;  in  a  forty-eight-year-old  man  there  occurred,  after  a  cataract 
operation,  at  the  same  time  as  severe  neuralgic  pains  of  the  right  half  of  the 
face,  sugar  in  the  urine  up  to  2^^  per  cent.  As  the  pains  ameliorated,  the 
sugar  disappeared  and  ten  years  later  the  man  was  still  sugar-free.  It  is  also 
known  that  cases  of  sciatica,  especially  those  with  frequent  attacks,  frequently 
show  alimentary  glycosuria.  H.  Strauss  found  [urines  tested  for  alimentary 
glycosuria]  in  three  cases  positive,  and  then  when  the  painful  attacks  were 
over,  negative  in  the  same  patients.  Much  cited  is  also  the  case  of  Frerichs, 
concerning  a  shot  injury  of  the  sciatic  nerve  with  severe  attacks  of  pain, 
during  which  sugar  always  appeared  in  the  urine.  As  the  suffering  amelio- 
rated the  sugar  disappeared  entirely.  It  might  be  possible  that  in  such  cases 
the  irritation  passes  away  along  the  sympathetic  nervous  system  through 
irradiation.  We  do  not  know  certainly  as  yet  as  to  whether  longer  con- 
tinuing glycosuria  may  originate  through  involvement  of  the  splanchnics 
or  the  great  gangHa  of  the  sympathetic  as  the  result  of  chronic  inflammatory 
processes — impaction  in  hard  tissue,  hemorrhages,  etc.  In  the  cases  of  long 
continuing  glycosurias  of  high  grade  known  up  to  the  present  time,  and 
previously  detailed,  the  associated  involvement  of  the  pancreas  or  the  centers 
in  the  brain  stem  through  the  violent  concussion  cannot  be  excluded  entirely. 

I  now  turn,  finally,  to  the  third  question,  whether  in  the  wake  of  a  trauma 
a  chronic  or  eventually  a  later  recurring  diabetes  on  a  nervous  foundation, 


560  DISEASES    OF    THE    INSULAR   APPARATUS    OF    THE    PANCREAS 

is  conceivable.  It  seems  to  me  that  the  possibility  that  a  scar  formation 
exercising  irritation  on  the  centers  regulating  sugar  metabolism  cannot 
entirely  be  ruled  out,  as  I  have  already  signified.  But  at  all  events  severe 
diabetes  of  year-long  duration,  that  is  progressive  and  eventually  ends  in  a 
coma,  cannot  be  explained  by  it.  If  the  diabetes  after  the  trauma  is  chronic, 
it  is  indeed  very  probable  that  a  predisposition  [Anlage]  for  diabetes  has 
existed  beforehand. 

Although  we,  in  the  previously  detailed  cases  of  organic  alterations  of  the 
brain,  must  regard  it  as  extremely  unlikely  that  an  acute  alteration  of  the 
pancreas  should  exist  at  the  same  time,  this  (factor)  cannot  be  excluded  in 
those  cases  of  brain  syphilis  which  are  also  designated  "nervous."  The 
cases  are  so  interesting  that  I  would  like  to  discuss  them.  In  i860,  Leiidet 
first  described  such  a  case.  It  was  that  of  a  thirty-two-year-old  woman,  who 
four  years  previously  had  progressed  as  far  as  the  development  of  a  "saddle 
nose."  In  her  there  developed  rather  suddenly  polyuria  and  polydipsia,  un- 
consciousness, paralysis  of  the  eye-muscles,  left-sided  anesthesia,  etc.  In  the 
urine  was  abundance  of  sugar.  On  the  institution  of  a  potassium  iodide  treat- 
ment the  diabetes  insipidus  and  glycosuria  disappeared,  and  also  the  brain 
symptoms  ameliorated.  Later,  with  a  more  recent  aggravation  of  the  brain 
symptoms,  polyuria  occurred  again,  but  not  sugar.  Autopsy  showed  that 
the  choroid  plexus  was  adherent  to  the  left  border  of  the  calamus  scriptorius, 
and  the  brain  substance  of  this  was  "eroded."  In  the  book  by  i^rmc^j 
are  reported  three  cases  of  lues  with  brain  symptoms  and  in  part  associated 
with  very  severe  diabetes,  in  which  diabetes  disappeared  under  antiluetic 
treatment,  or,  as  in  one  case,  improved  considerably.  Very  instructive 
cases  are  reported  by  Dub  and  Lemonier.  I  would  like  to  mention  more  in 
detail  the  case  of  Hemplenmacher.  In  a  forty-two-year-old  woman  who  had 
been  infected  with  syphilis  thirteen  years  previous  there  developed,  at  the 
same  time  with  a  polydipsia  and  pollakisuria,  a  left-sided  hemiplegia  with 
severe  headache.  In  the  urine  was  found  3.6  per  cent,  of  sugar.  Under  the 
inunction  treatment  and  potassium  iodide  the  glycosuria  gradually  disap- 
peared without  the  retention  of  an  antidiabetic  regime.  Also  the  brain 
symptoms  gradually  ameliorated,  and  later  complete  cure  was  obtained. 

In  this  and  in  other  cases  there  without  doubt  exists  a  causal  connection 
between  lues  and  diabetes.  The  occurrence  of  diabetes  simultaneously 
with  tertiary  luetic  symptoms,  the  cure  of  diabetes  by  antiluetic  treatment 
without  alteration  of  the  diet  alone  allows  of  no  other  conclusion.  On  the 
other  hand  the  interpretation  of  the  condition  as  nervous  diabetes  is  entirely 
uncertain,  as  a  simultaneous  alteration  of  the  pancreas  is  not  to  be  excluded. 
It  is  true  that  never  was  the  occurrence  of  absorptive  disturbances  mentioned, 
but  the  fact  cannot  be  excluded  that  the  insular  apparatus  may  alone  have 
been  damaged  in  its  function;  the  case  of  Mancliot,  moreover,  that  ran  along 
without  brain  symptoms  showed  likewise  no  absorptive  disturbances. 


THEORETICAL  CONCLUSR'"E  CONSIDERATIONS  56 1 

Theoretical  Conclusive  Considerations 

Before  I  finally  turn  to  the  question  as  to  what  signification  the  internal 
secretion  of  the  pancreas  has  for  the  pathogenesis  of  human  diabetes,  I 
should  like  briefly  to  summarize  the  most  important  points  that  were  touched 
upon  in  the  course  of  the  exposition. 

1.  Embryology,  anatomy,  experimental  pathology,  and  clinical  observa- 
tion point  to  a  certain  independence  of  the  insular  apparatus.  The  em- 
bryological  investigations  showed  that  the  insular  apparatus  and  the  acini 
developed  separately.  The  anatomical  investigation  showed  a  dift'erent  struc- 
ture of  these  two  apparatus;  a  transition  of  the  one  tissue-element  into  the 
other  has  not  up  to  the  present  been  demonstrated  with  certainty.  The  ex- 
perimental pathological  investigations  showed  that  after  ligation  of  the  excre- 
tory ducts  the  acini  become  destroyed,  while  the  insular  apparatus  for  the  most 
part  behaves  refractorily.  The  pathological-anatomical  observation  likewise 
showed  that  on  the  one  hand  the  insular  apparatus  ordinarily  is  more  resistant 
to  certain  destructive  processes  and  that  on  the  other,  isolated  alterations  of 
the  insular  apparatus  occur;  finally  clinical  observations  showed  that  dis- 
turbances in  the  function  of  the  glandular  apparatus  and  the  insular  appara- 
tus occur  entirely  apart  from  each  other,  and  that  to  such  isolated  disturb- 
ances a  corresponding  pathological-anatomical  finding  can  with  probabifity 
be  ascribed. 

2.  After  the  complete  extirpation  of  the  pancreas  always  occurs  (in  the 
dog)  a  characteristic  disturbance  of  metabolism;  there  always  develops  a 
severe  diabetes  leading  to  death,  in  the  course  of  which  aft'ection  the  gly co- 
genesis  is  to  a  high  degree,  but  not  entirely,  prevented  in  the  liver  and 
muscles;  the  disturbances  in  the  assimilation  of  sugar  might  lead  immediately 
to  a  disturbance  in  the  combustion  of  sugar.  In  addition  to  this  disturbance 
in  anabolism  exists  a  severe  disturbance  in  catabolism,  that  aft'ects  not  only 
the  carbohydrate  metabolism  (increased  sugar  production),  but  also  the 
protein,  fat,  and  salt,  metabolism.  The  catabolic  disturbance  shows,  on 
extirpation  of  the  pancreas,  great  regularity;  there  further  exists  regularly  a 
certain  hyperexcitability  of  the  sympathetic  nerves. 

3.  The  investigation  of  the  metabolism  in  human  diabetes  shows  disturb- 
ances in  both  anabolism  and  catabolism;  the  latter,  however,  confine  them- 
selves only  to  the  sugar  metabolism,  while  quantitatively  increased  breaking 
up  of  albumin  and  fat  are  not  demonstrated  even  in  the  severer  cases.  On 
the  contrary,  catabolic  disturbances  in  the  sugar  metabolism  are  much 
more  severe  in  the  graver  cases,  as  the  glycosuria  attains  a  much  greater 
intensity  than  in  the  dog  without  a  pancreas. 

4.  Concerning  the  nervous  manifestations  in  human  diabetes,  we  can 
distinguish  two  types,  between  which  we  find  all  possible  transitions.  In  the 
first,  rarer,  type,  to  which  v.  Noorden  has  lately  directed  attention,  the  nerv- 

36 


562  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

ous  manifestations  are  strongly  in  the  foreground  from  the  beginning.  Be- 
fore everything  is  the  psychic  factor,  that  under  circumstances  dominates 
the  elimination  of  sugar  from  the  beginning  up  to  even  years,  or  at  least 
influences  it  to  a  marked  degree.  Especially  accentuated  does  the  nervous 
factor  enter  into  certain  psychoses,  into  traumatic  neuroses,  into  severe 
attacks  of  pain,  etc.  But  this  can  be  the  case  in  even  uncomplicated  cases  of 
human  diabetes.  In  such  cases  it  would  perhaps  be  possible  to  demonstrate 
regularly  a  hyperexcitability  of  a  certain  part  of  the  sympathetic  system; 
especially  does  the  glycosuric  action  of  adrenalin  always  seem  in  such  cases 
to  be  distinctly  present,  indeed  under  circumstances  the  entire  complex  of 
adrenalin  action  (vascular  and  cardiac  manifestations,  etc.),  seems  to  be  very 
decidedly  pronounced.  There  are  all  the  transitions  between  this  and  hyper- 
tonic diabetes,  in  which  in  addition  to  the  hyperexcitability  of  the  sympathetic 
nervous  system,  there  also  occur  conditions  of  permanent  hyperexcitability. 

In  the  much  more  frequent  second  type  the  alimentary  factor  is  in  the  fore- 
ground from  the  beginning.  It  governs  the  intensity  of  the  elimination  of 
the  sugar,  whereas  psychical  factors  have  no  distinct  influence  on  this. 
Especially  are  there  no  manifestations  of  hyperexcitability  of  the  sympathetic 
system,  especially  that  apparatus  which  has  to  do  with  the  regulation  of 
sugar  metabolism.  In  the  later  stages  of  this  type,  when  it  has  developed 
to  severe  diabetes,  there  occur  a  series  of  symptoms  that  point  to  a  hyper- 
excitability of  the  sympathetic  system.  Then  adrenalin  can  make  the 
glycosuria  distinctly  more  intense  or,  if  the  patient  has  been  rendered  sugar- 
free,  may  call  forth  glycosuria.  Further  there  then  begins  an  especial 
sensitiveness  of  the  renal  vessels,  in  that  adrenalin,  or  similar  agents,  like 
pituitrin,  then  act  diuretically.  Finally  there  now  shows  itself  the  note- 
worthy phenomenon  that  long  continued  administration  of  thyroidin  raises 
the  blood-pressure,  without  eliciting  any  stronger  manifestations  of  hyper- 
thyroidism than  when  it  is  used  in  non-diabetic  individuals.  This  phenome- 
non seems  to  indicate  an  especial  lability  of  the  sympathetic  nervous  system. 
To  this  is  added  in  severe  diabetes  the  known  erethism  of  the  vessels,  the 
genesis  of  which  is  hard  to  account  for;  finally  I  would  like  to  point  out  a 
symptom  that  seems  to  me  to  belong  at  this  place;  it  is  the  extraordinary 
richness  in  blood  of  the  liver,  which  we  see,  as  already  Klcbs  mentioned, 
in  the  individuals  dead  from  severe  diabetes. 

All  these  manifestations  are  common  to  the  later  stages  of  both  types; 
I  would  believe  that  they  are  more  markedly  pronounced  in  the  later  stages 
of  the  first  type.  Yet  for  the  corroboration  of  this  is  necessary  a  greater 
material  than  has  been  observed  up  to  the  present. 

Let  us  now  investigate  how  far  the  pathologico-anatomical  findings  suffice 
to  explain  the  clinical  observations.  No  doubt  there  are  cases  with  gross 
anatomical  disturbances  of  the  pancreas  and  especially  of  the  insular  appara- 
tus, that  without  an}'thing  else  explain  a  severe  disturbance  of  function  of  the 


THEORETICAL    CONCLUSIVE    CONSIDERATIONS  563 

same.  Such  cases  rightly  deserve  the  name  pancreato genie  diabetes.  There 
are  further  described  in  detail  cases  of  alterations  of  the  central  nervous  sys- 
tem, whose  seat  makes  appear  intelligible  long  continuing  irritative  mani- 
festations on  the  part  of  the  sympathetic  centers,  which  have  to  do  with  the 
regulation  of  metabolism,  or  perhaps  on  the  part  of  the  paths  that  bind  these 
with  the  chromaffin  tissue.  It  is  doubtful  whether  a  permanent  diabetes 
may  become  manifest  through  such  gross  anatomical  disturbances.  In 
addition  there  exists  a  great  many  cases  in  which  nothing  certain  is  found  in 
the  nervous  system  and  the  insular  apparatus  shows  only  relatively  slight 
alterations.  If  we  accept  the  viewpoint  of  Weichselbaum,  however,  it  seems 
to  me  that  up  to  the  present  there  has  been  in  such  cases  an  insufficient  agree- 
ment between  the  pathologico-anatomical  findings  and  the  intensity  and 
acuteness  of  the  clinical  manifestations.  Especially  would  this  hold  true  for 
the  juvenile  uncontrollably  progressive  cases  of  diabetes  mellitus.  In  such 
cases  there  lies  close  the  thought  of  a  congenital  weakness  in  the  rudiment 
[Anlage]  of  the  insular  apparatus,  whereby  the  hereditary  and  famihal  occur- 
rence may  become  more  intelligible.  We  can  also  suppose  that  in  such 
individuals  various  deleterious  influences — infections  and  intoxications, 
etc. — find  a  locus  resistentias  minoris  and  damage  the  insular  apparatus; 
and  we  can  further  suppose  that  the  same  alterations  of  the  insular  apparatus 
may  recuperate,  especially  if  by  reason  of  a  corresponding  dietetic  treatment 
or  prophylaxis  the  damaged  organ  is  given  time  and  rest  for  recovery. 

It  appears,  however,  that  through  these  means  of  consideration  alone  the 
problem  of  human  diabetes  will  not  become  solved.  The  nervous  factor  that, 
as  chnical  observation  teaches,  often  occupies  the  foreground,  assigns  to  the 
nervous  system  a  much  more  important  role.  A  disturbance  of  the  regulation 
of  sugar  metabolism  through  the  central  nervous  system  is  especially  to  be 
thought  of  in  two  directions.  Either  the  activity  of  the  insular  apparatus 
may  be  deficient  thereby,  so  that  the  nervous  impulses  necessary  for  a  normal 
function  are  too  weak — an  insufficiency  on  a  nervous  basis,  such  as  we  know 
in  the  glands  with  an  external  secretion  in  achylia  gastrica,  for  instance.  It 
appears  to  me,  however,  that  according  to  that  which  I  have  previously  set 
forth  concerning  the  nervous  type,  this  assumption  has  little  a  priori  to 
recommend  it.  Or  in  the  metabohsm  of  sugar  there  may  be  an  increase  in 
catabolism  through  an  enormous  excitation  of  those  centers  which  regulate 
the  activity  of  the  chromafiin  tissue.  We  can  designate  this  type,  then,  as 
nervous  or  adrenalino genie.  I  would  only  point  out  especially  that  in  this 
type  the  insular  apparatus  is  entirely  intact.  That  such  an  excitation  of  the 
nervous  centers  leads  to  a  continuous  and  strong  glycosuria,  brings  into  relief 
a  certain  weakness  of  the  insular  apparatus.  In  individuals  with  completely 
normal  pancreas,  such  excitations  as  increase  the  catabolic  processes  are 
neutralized  by  the  corresponding  counter-regulations.  The  difficult  feature 
of  the  question  seems  much  more  to  lie  in  the  fact  that  in  the  nervous  type 


564  DISEASES    OF    THE    IXSULAR    APPARATUS    OF    THE    PANXREAS 

this  condition  of  h\-perexcitability  seems  to  occur  primarily  and  that  it  in- 
creases the  disturbance  in  metabolism  in  a  manner  that  is  hardly  possible 
through  failure  of  the  insular  apparatus  alone,  while  it  accompanies  the  pure 
pancreogenic  type  only  secondarily  and  perhaps  in  a  less  intense  form.  That 
also  in  the  nervous  type  an  increased  adrenalin-contents  of  the  blood  could 
not  up  to  the  present  be  demonstrated,  seems  to  me  to  signify  nothing  against 
this  assumption;  on  the  one  hand,  the  biological  methods  up  to  the  present 
have  been  insufficient  for  the  demonstration  of  adrenalin  in  the  serum  (I  refer 
to  the  work  of  O'Connor,  Priestly,  Fleming,  Kahn  and  myself)  and  on  the  other 
hand  we  can  conceive  that  on  insufficient  contraregulation  also  minimal  sur- 
plus production  of  adrenalin  already  produces  a  significant  effect  on  sugar 
metabolism. 

As  to  the  cause  of  such  an  abnormal  excitation  in  the  nervous  system  we 
know  as  yet  nothing.  We  have,  however,  met  with  similar  conceptions  in  the 
diseases  of  the  other  ductless  glands.  I  refer  to  Basedow's  disease  where 
especially  in  the  peracute  cases,  the  increase  of  function  of  the  thyroid  gland  is 
ascribed  by  many  authors  to  a  central  excitation;  and  indeed  they  regard 
many  symptoms  as  coordinate  with  hyperthyroidism,  and  conditioned  cen- 
trally. We  could  designate  the  entire  disease  picture  as  hyperthyrosis.  and 
the  important  syndrome  conditioned  b>-  the  hyperfunction  of  the  thyroid 
gland  we  could  designate  hyperthyroidism.  According  to  this  hypothesis  we 
could  regard  these  hyperfunctional  conditions  of  the  ductless  glands  as  neu- 
roses. So  far  as  this  theory  of  diabetes  is  concerned,  we  are  unmistakably 
approaching  again  the  view  first  propounded  by  the  genial  investigator  of 
diabetes,  Claude  Bernard,  although  in  a  considerably  modified  form. 

If  we  now  on  the  basis  of  the  developed  view,  finally  turn  to  the  question 
as  to  why  the  diabetes  of  dogs  without  their  pancreas  deviates  in  some  essen- 
tial points  from  that  of  the  genuine  human  diabetic  it  seems  to  be  that  as  yet  a 
satisfactory  explanation  has  not  been  possible.  The  principal  dift'erence  lies 
in  the  fact  that  in  the  dog  without  a  pancreas  the  catabolic  factor  of  the  car- 
bohydrate metabolism  is  less  strong,  that  of  the  fat  and  protein  metabolism 
more  strong,  while  in  genuine  human  diabetes  the  first  is  more  strongly  de- 
veloped, and  the  latter  factors  fail  almost  entirely.  Perhaps  there  may  after 
all  be  ehcited  some  grounds  for  the  explanation  of  this  considerable  dift"erence. 
On  the  one  hand  it  might  not  be  impossible  that  in  the  carnivorous  dog  the 
significance  of  the  inner  secretion  of  the  pancreas  is  not  quite  the  same  for  the 
metabolism  as  in  the  omnivorous  human  being. 

We  must  then  assume  that  in  the  dog  the  pancreatic  hormone  exercises 
also  a  direct  inhibiting  influence  on  the  splitting  up  of  protein  and  fat.  A 
certain  decision  of  this  question  if  exact  observations  of  sudden  and  complete 
absence  of  pancreas  [function]  in  man  were  at  hand,  which  up  to  the  present 
has  not  been  the  case. 

On  the  other  hand  the  following  idea  might  \erv  well  be  elicited  from  what 


THEORETICAL    CONCLUSIVE    CONSIDERATIONS  565 

has  been  said :  In  experimental  pancreatic  diabetes,  only  the  pancreas  is  absent, 
all  the  rest  of  the  manifestations  are  secondary;  in  genuine  human  diabetes  there 
exists,  however,  a  disease  of  the  whole  apparatus  regulating  sugar  metabolism 
{nervous  centers  in  the  medulla  and  brain  stem,  connecting  paths,  pancreas,  and 
chromaffin  tissue)  with  insufficiency,  but  not  complete  absence,  of  one  part  and 
more  or  less  independent  hy  per  excitability  in  the  other  part. 

Through  this  view,  which  has  been  the  product  of  v.  Noorden's  clinic  in 
recent  years,  the  problem  of  the  pathogenesis  of  diabetes  mellitus  has  been 
broadened,  but  the  solution  of  it  seems  only  to  have  been  thrust  back  one 
step  further. 

As  far  as  the  other  glands  are  concerned  in  the  bringing  about  of  diabetic 
glycosuria,  we  may  off-hand  ascribe  with  certainty  an  important  role  in  this 
direction  to  only  two  other  glands,  the  thyroid  and  the  hypophysis.  There 
exists,  however,  but  littler  clearness  in  which  way  these  ductless  glands  enter 
into  the  regulative  mechanism  of  sugar  metabolism,  and  whether  they  exer- 
cise this  influence  chiefly  or  exclusively  by  way  of  the  pancreas.  In  the  chap- 
ter on  Basedow's  disease  we  found  that  hyperthyroidism  was  not  rarely 
associated  with  a  reduction  of  the  assimilation  limits  for  carbohydrates;  in- 
deed, under  circumstances,  it  could  lead  to  spontaneous  glycosuria.  The 
circumstance  that  the  alimentary  factor  is  so  prominent  in  these  cases, 
speaks  for  the  fact  that  through  the  hyperthyroidism  there  is  called  forth  an 
insufficiency  of  the  pancreas;  further,  the  circumstance  that  with  the  suppres- 
sion of  the  hyperthyroidism  the  glycosuria  again  disappears  and  eventually 
there  come  about  normal  relations,  shows  that  this  insufficiency  is  actually  the 
result  of  hyperthyroidism.  It  appears  therefore  as  has  already  been  amplified 
in  the  chapter  on  Basedow's  disease,  that  hyperthyroidism  seems  to  signify  a 
functional  overloading  of  the  pancreas;  it  is  intelligible,  from  this  standpoint, 
that  glycosuria  sets  in  only  in  individuals  predisposed  to  it.  As  without  such 
a  functional  overloading  glycosuria  would  never  occur,  we  are  well  justified 
in  speaking  of  a  thyrogenic  glycosuria  in  such  cases.  This  also  is  mostly 
easily  delimited  from  true  diabetes  complicated  with  Basedow's  disease. 

As  far  as  the  diabetic  glycosurias  that  occur  so  frequently  in  acromegaly 
and  gigantism  are  concerned,  it  has  already  been  set  forth  in  the  correspond- 
ing chapter  that  there  is  present  in  the  great  majority  of  cases  an  organic 
disease  of  the  insular  apparatus.  It  was  mentioned  there  that  in  all  conditions 
of  hyperfunction  of  the  glandular  hypophysis  a  period  of  an  abnormal  tend- 
ency to  growth  is  followed  by  a  period  of  decay,  and  that  the  entrance  of  this 
decline  is  different  in  the  various  organs  and  especially  so  in  the  various  duct- 
less glands.  The  insular  apparatus  appears  to  be  especially  sensitive.  Be- 
sides these  true  diabetic  glycosurias  there  is  present  in  rare  cases  of  acromegaly 
a  similar  condition  to  that  observed  in  true  thyrogenic  glycosurias ;  in  these 
cases  right  at  the  beginning  of  the  disease  there  develops  a  glycosuria,  which 
later  disappears  and  gives  place  to  a  normal  assimilative  ability.     Whether 


566 


DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 


this  glycosuria  is  of  thyrogenic  origin  or  whether  the  h\"pophysis  enters 
not  in  some  other  manner  directly  into  the  regulatory  mechanism  of  the 
carbohydrate  metabolism,  I  shall  not  touch  upon. 

V.  Xoorden  has  portrayed  the  influence  of  the  ductless  glands  upon  the 
regulation  of  the  carbohydrate  metabolism  in  the  following  scheme.  I  have 
modified  it  in  that  I  have  added  to  it  two  connecting  lines — one  between 
the  chromatin  tissue  and  the  tissue  at  the  periphery  (chiefly  the  muscular 
system)  and  one  between  pancreas  and  tissue.  This  lends  expression  to  the 
opinion  that  pancreas  and  chromaffin  tissue  directly  regulate  the  assimila- 
tion and  dissimilation  of  carbohydrates.  Let  me  call  attention  to  the 
fact  that  the  line  of  connection  between  thyroid  gland  and  pancreas  is 
meant  to  express  only  the  fact  that  increased  thyroid  activity  disturbs  the 
equilibrium  to  the  disadvantage  of  the  pancreas.  WTiether  this  happens 
Centr  TkvroUi-     through  the  influencing  of  the  activity 

of  the  insular  apparatus  or  through  in- 
fluencing the  ultimate  organs  affected 
is  still  uncertain. 

"The  line  of  dashes  represents  nerve 
paths;  the  solid  lines  represent  blood  paths. 
The  arrows  show  the  direction  of  the  ex- 
citation; the  signs  -|-  or  —  behind  them 
mean  whether  the  stimulus  transmitted  by 
the  respective  path  increases  or  diminishes 
the  specific  activity  of  the  organ  in  ques- 
tion," whether  it  acts  assimilatorily  or 
dissimilatorily. 

Differential  Diagnosis. — A  sharp 
separation  of  the  ephemeral  or  transi- 
tory glycosurias  from  true  diabetes  is  not  practical.  There  are  fleeting  tran- 
sitions between  these  forms.  We  would  naturally  not  regard  every  individual 
who  has  one  time  eliminated  grape-sugar  in  his  urine  as  a  diabetic;  otherwise 
if  investigations  as  to  alimentary  glycosuria  (loo  gm.  grape-sugar)  carried  out 
at  great  intervals  result  always  negatively,  we  could  with  justification  speak 
of  the  cure  of  the  diabetes. 

We  would  think  in  general  of  a  pancreatogenic  diabetes  when  the  alimen- 
tary factor  comes  strongly  in  the  foreground;  especially  if  pancreatogenic 
resorptive  disturbances  are  present;  further  in  all  those  conditions,  which 
according  to  experience  favor  infection  of  the  pancreas;  hence  in  cholelithia- 
sis, pancreatic  stones,  also  in  lues,  cirrhosis  of  liver,  and  arteriosclerosis, 
etc.  Hirschfeld  regards  also  the  behavior  of  diuresis  as  a  differential  diag- 
nostic factor.  It  is  not  unlikely  that  in  true  pancreatic  diabetes  there  is 
at  the  beginning  no  polyuria. 

In  glycosurias  that  occur  during  the  course  of  infectious  diseases,  there 
is  indeed  much  that  speaks  for  the  involvement  of  the  pancreas  in  the  infec- 


Fancreas 


THEORETICAL    COXCLUSR"E    COXSTDER-ITIOXS  567 

tion;  there  is  much,  for  the  thought,  however,  that  the  violent  conditions  of 
excitation  in  the  vegetative  nervous  system  may  be  of  significance  for  the 
genesis  of  a  nervous  glycosuria. 

For  the  assumption  of  a  nervous  gtycosuria  there  are  brought  about 
s\Tnptoms  that  indicate  a  disease  of  the  pons,  cerebellum,  and  medulla  ob- 
longata, perhaps  also  circumstances  that  can  bring  about  an  irritation  of  the 
splanchnics  or  the  great  s\Tapathetic  ganglia  either  directly  or  by  circuitous 
routes;  especially,  then,  severe  neuralgias.  Further  we  have  to  turn  our 
especial  attention  to  the  behavior  of  the  vegetative  nervous  system  and  the 
influencing  of  the  glycosuria  through  the  psyche.  In  many  cases  we  can 
perhaps  carry  out  the  test  for  adrenahn  glycosurias  (in  the  aglycosuric  con- 
dition) or  Ldun's  reaction;  high-grade  pohTiria  as  weU  as  simultaneously 
existing  h}-pertonia  speak  for  the  nervous  form  or  for  a  marked  associated 
involvement  of  the  nervous  system. 

Finally,  as  to  the  th}Togenic  form,  naturally  we  must  take  pains  to 
detect  S}Tichronous  systems  of  h^-perth^Toidism.  I  would  mention  that  in 
all  the  cases  of  true  th\Togenic  glycosuria  that  I  have  seen,  the  eye  symptoms 
were  at  most  indicated.  But  tremor,  sweats,  and  mononucleosis  of  the  blood 
were  always  present.  A  higher  degree  of  glycosuria  speaks  well  against  the 
purely  th}Togenic  origin.  Fat  stools  with  strikingly  good  sphtting  of  the  fat 
and  abundant  soap-contents  speak  for  the  thyrogenic  glycosuria.  The  diag- 
nosis would  be  assured,  if  with  the  retrogression  of  the  h}-perth}Toidism 
(spontaneously  or  by  means  of  Rontgen  illumination,  etc.  .  the  glycosuria 
disappeared  altogether,  and  if  now  strong  loading  of  the  carbohydrate 
metaboKsm  no  longer  led  to  elimination  of  sugar. 

To  close  with  some  therapeutic  points  of  ^^.ew.  In  pancreatogenic  dia- 
betes the  dithcult  feature  of  the  treatment  up  to  the  present  lies  in  the  diet. 
which  purposes  to  avoid  [the  functionating  of]  the  diseased  organ.  This 
is  brought  about  by  limitation,  or  even  by  temporary  complete  withdrawal 
of  the  supply  of  carbohydrates  and  by  simultaneous  limitation  of  the  supply 
of  proteins.  Also  in  cases  with  ketonuria.  an  abundant  supply  of  fat  should 
be  avoided.  The  patient  should  be  made  free  of  sugar,  and  when  possible, 
maintained  sugar-free.  There  often  occurs  in  such  cases  a  restoration  of 
the  insular  apparatus;  if  later  than  the  investigation  shows  that  the  assim- 
ilatory  ability  has  significantly  increased,  carbohydrates  should  again  be 
administered  at  times  in  order  to  avoid  permanent  poverty  in  glycogen.  The 
great  significance  of  r.  Noordens  oat-meal  treatment  lies  in  the  fact  that  in 
an  indiAidual  under-nourished  with  carbohydrates  large  quantities  of  gly- 
cogen are  administered  as  an  increment.  Thus  is  often  explained  the  wonder- 
ful action  on  the  ketonuria.  The  cataboKsm  becomes  hmited.  In  the  severe 
forms  the  complete  withdrawal  of  carbohydrates  is  not  possible  perma- 
nently, as  the  complete  absence  of  glycogen  increases  the  formation  of 
ketone  bodies  entirelv  too  markedlv.     Here  we  must  trv  to  restrict  the  slv- 


568  DISEASES    OF    THE    INSULAR    APPARATUS    OF    THE    PANCREAS 

cosuria  at  least  as  much  as  possible,  and  counteract  the  overloading  with  acids 
by  alkali  therapy. 

Much  indeed  speaks  for  the  fact  that  in  the  nervous  form  too  vigorous 
dietetic  measures  act  unfavorably,  although  v.  Xoorden  points  out  that  in 
such  cases  a  weakness  of  the  insular  apparatus  may  always  be  supposed,  which 
tends  to  come  to  the  fore  in  the  further  course,  and  therefore  that  a  complete 
disregard  for  prophylactic  dietary  prescriptions  may  be  disastrous  for  the 
patients.  In  the  pure  thyrogenic  form  the  treatment  of  the  hyperthyrosis 
occupies  the  foreground,  in  the  pursual  of  which,  however,  A-igilance  in  a 
dietetic  respect  is  not  excluded.  The  treatment  of  diabetes  in  acromegaly 
should  coincide  with  that  of  genuine  diabetes. 

Addendum 

AUoi.  in  his  book  on  "Glycosuria  and  Diabetes,"  draws  an  essential 
distinction  between  these  two  conditions,  pointing  out  that  in  nondiabetic 
animals  the  limits  of  tolerance  are  apparent,  not  real,  and  that  in  these  ani- 
mals there  is  no  real  limit  to  the  power  of  utilization  of  the  sugar  except  death. 
Also  that  in  the  various  forms  of  glycosuria  dextrose  always  produces  a 
hmitation  of  the  amount  of  urine,  never  a  diuresis  as  in  diabetes.  He  divides 
diabetes  by  pancreatic  operation  into  a  diabetes  gravis  and  a  diabetes  levis, 
according  to  whether  dextrose  is  or  is  not  excreted  on  meat  diet,  and  each 
of  these  into  a  permanent  and  a  transient  form.  Permanent  diabetes  gravis 
and  transient  diabetes  levis  are  absolute  terms;  but  transient  diabetes  gravis 
and  permanent  diabetes  levis  are  relative,  the  two  conditions  passing  into 
each  other.  These  various  types  depend  on  the  condition  of  the  pancreatic 
remnant.  The  ways  that  diabetes  could  be  produced  when  the  pancreas 
remnant  is  of  more  than  ordinary  size  are  by  an  irritative  nervous  lesion,  such 
as  the  Bernard  puncture,  and  by  circulatory  disturbances  in  the  pancreas. 
The  fact  that  the  nervous  system  can  influence  the  pancreatic  hormone,  as  is 
practically  also  Fallals  conclusion,  seems  to  the  editor  to  speak  in  favor 
of  Criles  contention  that  diabetes  may  be  conditioned  centrally,  the  nerve 
cells  showing  chromatolytic  changes.  At  all  events  the  intermediation  of 
the  islands  of  Langerhans  of  the  pancreas  remain  unquestioned,  this  bringing 
about  a  deficiency  of  what  Allen  terms  "pancreatic  amboceptor."  Accord- 
ing to  Allen  s  experiments  there  occurs  in  diabetes  not  a  change  in  the  hepatic 
cells  that  cause  them  no  longer  to  fix  dextrose,  but  a  change  in  the  physical 
state  of  dextrose  itself.  Instead  of  combining  with  a  colloidal  ''pancreatic 
amboceptor"  to  be  in  a  condition  to  be  utilized,  it  maintains  its  ordinary 
crystalloidal  properties,  thus  causing  diuresis.  Whether  there  is  any  dis- 
tinction between  pancreatic  hormone  and  the  pancreatic  amboceptor  does 
not  seem  very  clear  in  a  cursory  review  of  Allen^s  voluminous  work.  Allen 
seems  to  call  the  substance  an  amboceptor  because  it  acts  as  an  intermediary 
body  between  the  dextrose  and  various  body  cells.  It  has  in  common  with 
hormones,  at  all  events,  the  fact  that  it  is  an  internal  secretion,  dependent 


ADDEKDTJM  569 

on  the  integrity  of  the  insular  apparatus  of  the  pancreas.  Evidence  is  brought 
forward  that  at  least  one  form  of  diabetes  insipidus  is  associated  with  cir- 
culatory disturbances  of  the  pancreas  (how  is  this  diabetes  insipidus  to  be 
correlated  with  the  polyuria  approaching  a  diabetes  insipidus  that  occurs  in 
certain  h}'pophysial  affections?),  but  that  is  not  associated,  as  is  diabetes 
mellitus,  with  any  evidence  of  insular  involvement. 

It  is  probable  that  the  good  results  of  oats  on  diabetes  are  due  to  the  fact 
that  rest  is  provided  for  the  pancreas.  According  to  Allen:  by  reason  of 
freedom  from  harmful  stimuli  from  the  intestine,  also  perhaps  by  reason  of  a 
diminished  labor  of  external  secretion,  and  possibly  by  reason  of  a  mild 
beneficial  stimulation  in  a  positive  sense,  the  pancreas  is  able  to  perform 
its  function  of  internal  secretion  more  efficiently,  and  the  diabetic  condi- 
tion is  correspondingly  benefited.  This  explanation  agrees  with  facts  in  the 
literature. 

On  the  strength  of  his  experiments,  Allen  has  recently  advocated  and 
practised  with  good  results  a  method  of  treatment,  which  consists  in  absti- 
nence from  food  and  drink,  doses  of  alcohol  (not  absolutely  essential),  and 
the  administration  of  sodium  bicarbonate.  This  regime  is  continued  for 
twenty-four  to  forty-eight  hours  after  the  absolute  disappearance  of  sugar 
from  the  urine  f which  occurs  in  from  one  to  eight  days),  when  it  is  replaced 
with  10-40  gm.  of  carbohydrates  in  the  form  of  steamed  green  vegetables 
^gradually  increased),  together  with  fats  and  proteins  (which  are  also  in- 
creased gradually).  As  soon  as  sugar  reappears  in  the  urine,  another  fast 
day  is  instituted.  Stengel.  Jonas  and  Austin  while  advocating  Allen's  treat- 
ment for  severe  cases  of  diabetes  sho-wing  high  ketonuria,  have  had  good 
results  in  the  milder  cases,  those  in  which  Allen's  treatment  is  perhaps  too 
severe,  by  placing  the  patient  on  a  carbohydrate-free  diet,  then  adding  green 
vegetables  to  this  diet,  and  later  allowing  carbohydrates,  below  the  limits  of 
tolerance.  The  days  of  the  carbohydrate-free  diet  are  to  be  spent  in  bed, 
at  rest. 

A  recent  study  of  the  h}-pophysis  in  diabetes  mellitus  by  Fry  has  shown 
that  it  exhibits  definite  histological  changes.  It  contains  adenomatous 
masses  of  eosinophile  cells,  and  there  is  colloid  invasion  of  the  anterior  lobe, 
together  -^ith  area  of  cellular  degeneration  in  this  part  of  the  gland. 

References 

Allen  (F.  M.).  Studies  concerning  gl3-cosuria  and  diabetes.  Boston,  1913,  X.  M. 
Leonard. 

Allen  (F.  M.).  Studies  concerning  diabetes.  Jr.  Am.  ]\I.  Ass.,  Vol.  LXIII,  Xo. 
II,  Sept.  12,  1914,  p.  939-943. 

Stengel  (A.),  Jonas  (L.),  and  Austin  (/.  H.).  The  treatment  of  diabetes  mellitus 
with  special  reference  to  Allen's  method.  Pennsjdvania  Medical  Journal.  Vol.  XIX, 
Xo.  4,  Jan.  1916,  p.  283—287. 

Fry  {H.  J .  B.).  The  pituitary  gland  in  diabetes  mellitus  and  disorders  of  the  glands  of 
internal  secretion.  The  Quarterly  Journal  of  Medicine,  Vol.  VIII,  X'o.  32,  July,  191 5, 
pp.  277-299. 


CHAPTER  XIV 

THE  DIFFERENT  FORMS  OF  OBESITY  AND  ADIPOSITAS 

DOLOROSA 

We  have  already  spoken  of  obesity  in  other  chapters.  It  seems  to  me 
appropriate,  however,  to  describe  the  relations  of  the  ductless  glands  to  the 
pathogenesis  of  obesity,  even  though  I  do  not  tell  anything  new.  Further, 
it  would  be  appropriate  to  discuss  the  relations  between  obesity  and  lipomato- 
sis, as  also  the  origin  of  lipomatosis  has  been  brought  into  relation  with 
disturbances  of  the  ductless  glandular  system. 

A.  THE  DIFFERENT  FORMS  OF  OBESITY 

Two  different  principal  types  of  obesity  have  been  distinguished 
{v.  Noorden,  Lorand),  exogenous  obesity  and  endogenous  obesity.  By  exogen- 
ous obesity,  Lorand  understands  the  obesity  of  big  eaters — that  which  later 
becomes  combined  with  diabetes;  endogenous  obesity  he  refers  to  a  disease 
of  the  ductless  glandular  system.  Such  individuals  are  for  the  most  part 
anemic,  have  an  ''unhealthy  fat,"  and  the  combination  of  the  disease  con- 
dition with  diabetes  belongs  to  the  great  rarities.  The  separation  and  char- 
acterization of  both  forms  has  been  carried  on  exhaustively  by  v.  Noorden 
in  his  monograph  on  obesity. 

According  to  v.  Noorden  exogenous  obesity  is  either  an  overfeeding  obesity 
or  a  laziness  obesity,  or  the  result  of  both  overfeeding  and  laziness  combined. 
Exogenous  obesity  often  occurs  familially  or  hereditarily,  although  v.  Noorden 
points  out  that  in  many  of  these  cases  there  has  been  much  more  the  heredi- 
tary transmission  of  a  habit  of  living  than  that  of  a  definite  constitution. 
Naturally,  cases  occur  that  must  be  regarded  as  transition  forms  between 
exogenous  and  endogenous  obesity.  A  further  entrance  into  the  subject  of 
exogenous  obesity  does  not  lie  within  the  confines  of  my  theme;  I  shall  refer 
to  the  exhaustive  exposition  of  :'.  Noorden. 

In  endogenous  obesity  much  value  has  been  laid  on  the  demonstration  of 
a  diminution  of  the  fundamental  exchange  and  great  pains  have  been  taken 
in  the  demonstration.  While  such  a  diminution  may  be  demonstrated  in 
myxedema  with  certainty  and  ease,  the  attempts  to  demonstrate  it  in  en- 
dogenous obesity  have  met  with  great  difficulties.  As  the  fat  tissue  only  takes 
part  in  internal  respiration  to  a  limited  degree,  the  fundamental  exchange 
must  fall  very  strongly  in  each  fat  individual  if  we  wish  to  calculate  it  per 
kilo  of  body  weight.     But  we  possess  no  method  of  estimating  the  fat  con- 

S70 


THE    DIFFERENT    FORMS    OF    OBESITY  571 

tents  of  an  individual,  but  must  rely  on  coarse,  insufficient  estimations. 
The  investigations  up  to  the  present  on  the  fasting  and  rest  values  of  corpu- 
lent individuals  (v.  Xoorden,  Tkiele  and  Xehring,  Stivce.  Magnus-Levy, 
Rubner,  Jacquet  and  Svenson,  Salomon.  Reach,  StaeheUn,  and  v.  Bergmami) 
have  been  subjected  to  an  analytical  criticism  by  :'.  Xoorden;  the  calculation 
of  the  exchange  per  kilo  of  body  weight,  must,  as  already  mentioned,  be 

.     ,     .  ,    .  .         Oo  consumption 

reiected  as  of  no  use.     The  calculation  ot  the  quotient  — , — -, — -, — ^^r- — 
•^  ^  body  height 

shows  in  corpulent  individuals  higher  values  sooner  than  in  normal  indi- 
viduals. This  is  perhaps  due  to  the  fact  that  in  heavy  accumulations  of  fat 
the  work  of  the  heart  and  of  the  respiratory  muscles  is  perhaps  made  more 
difficult.  V.  Xoorden  arrived  at  the  result  that  the  estimation  of  the  respira- 
tory exchange  at  rest  has  up  to  the  present  furnished  no  sure  decision  in  this 
question.  This  is  true  apparently  of  the  estimations  up  to  the  present  of  the 
factors  inlluencing  the  exogenous  respiration  gaseous  exchange.  The 
opinion  has  been  held  that  in  the  corpulent  the  ingestion  of  food  should 
call  forth  a  shghter  increase  of  the  exchange.  Herein  lies  a  tendency  to 
saving.  The  experiments  that  have  been  made  up  to  the  present,  however, 
do  not  bear  strict  criticism.  Up  to  the  present  only  the  determination  of 
the  calorie  requirements  has  led  to  reliable  results  in  some  cases.  The  supply 
of  heat  w^as  estimated  in  a  very  careful  manner  and  for  a  long  period,  and  it 
was  determined  that  corpulent  persons  either  take  on  fat  or  do  not  lose  it 
under  conditions  under  which  normal  persons  either  would  not  become  corpu- 
lent or  would  lose  in  body  weight.  In  this  method  care  should  be  taken  that 
exogenous  factors  are  not  allowed  to  take  a  part.  The  corpulent  individual, 
to  whom  every  movement  is  attended  with  exertion  and  is  disagreeable, 
has  often  learned  to  get  along  with  the  minimum  of  movement,  otherwise 
he  sits  and  stands  as  a  normal  individual.  To  this  must  be  added  also  the 
phlegm  of  such  individuals.  These  methods  can  thus  furnish  a  certain 
conclusion  as  to  the  diminution  of  the  fundamental  exchange,  if  extremely 
low  values  are  found.  This  is  actually  so  in  the  cases  reported.  Such  cases 
are,  however,  as  v.  Xoorden  has  pointed  out.  quite  rare. 

We  must  now  consider  the  question  as  to  whether  a  diminution  in  the 
fundamental  exchange  characterizes  endogenous  obesity,  and  whether  this  is 
necessary  for  the  assumption  of  a  case  as  such.  In  a  typical  myxedema  it  is 
true  that  simultaneously  with  the  reduction  in  the  fundamental  exchange 
there  occurs  an  increase  of  the  body  weight,  but  this  does  not  always  progress 
to  obesity.  It  is  much  more  probable  that  the  increase  in  weight  can  de- 
pend solely  or  in  great  part  on  the  accumulation  of  myxedematous  tis- 
sue and  the  water  accumulation.  In  normal  grown  individuals  the  ingestion 
of  food  rises  or  falls  with  the  greater  or  lesser  need  for  it.  The  body  weight, 
apart  from  slight  variations,  often  remains  the  same  for  years  at  a  time. 
This  depends  on  a  line  regulatory  mechanism  that  as  yet  has  not  been  investi- 


572  OBESITY    AND    ADIPOSITAS    DOLOROSA 

gated  sufficiently.  The  most  important  element  in  the  same  is  the  appetite, 
although  at  times  we  eat  very  much  more  than  the  appetite  really  craves 
for,  and  then  follows  a  period  not  of  lessened  appetite,  but  perhaps  of  in- 
creased demand  for  movement,  the  cause  of  which  is  not  known.  May 
not.  perhaps  on  the  occasion  of  too  great  demand  on  the  assimilation,  sub- 
stances arise  which  give  occasion  to  this  desire  for  movement?  If  now  the 
diminution  of  the  fundamental  exchange  increases  the  body  weight,  that  is, 
the  need  for  food  does  not  keep  pace  with  the  exchange,  it  seems  to  me  that  a 
diminution  of  the  fundamental  exchange  is  less  to  blame  for  this  increase  in 
body  weight  than  a  disturbance  of  the  regulatory  mechanism;  and  it  is  per- 
haps not  inconceivable  that  there  are  forms  of  endogenous  obesity  without 
diminution  in  the  fundamental  exchange.  In  exogenous  obesity,  according  to 
this  point  of  view,  the  regulatory  mechanism  is  disturbed  voluntarily  or 
on  account  of  bad  habits  {v.  Noorden);  in  endogenous  obesity,  involuntarily 
through  an  alteration  in  the  working  together  of  the  factors  governing  assimi- 
lation. If  now  I  investigate  how  far  such  factors  depend  on  the  function  of 
the  ductless  glands,  it  is  known  to  me  that  I  trespass  into  the  territory  of 
speculation,  yet  I  see  no  other  way  of  bringing  into  association  the  few  cer- 
tain observations  that  we  possess  on  this  question.  At  first  I  must  again  call 
to  mind  that  the  ductless  glands  exert  an  influence  on  both  the  endogenous 
and  the  exogenous  factors  of  the  total  exchange.  Upon  the  endogenous 
through  diminution  of  the  vegetative  functions,  for  example;  on  the  exogen- 
ous by  their  influence  on  the  temperament,  the  psyche,  the  desire  for  move- 
ments, etc. 

I.  Pancreatogenic  Obesity 

We  shall  consider  in  the  first  place  a  form  of  obesity,  whose  genesis 
has  yet  not  been  furnished  to  us.  It  is  observations  from  the  physiology 
and  pathology  of  metabohsm  that  makes  the  supposition  of  such  a  form  possi- 
ble; if  this  supposition,  however,  suffices,  many  other  forms  of  endogenous 
obesity  may  be  made  the  more  readily  intelligible  from  this  standpoint.  The 
complete  extirpation  of  the  pancreas  in  the  dog  leads  to  an  appreciable  in- 
crease in  the  gaseous  exchange.  High-grade  insufficiency  of  the  insular 
apparatus  in  man  is  not,  however,  associated  with  an  essential  raising  of  the 
heat-production.  Therefore,  if  although  up  to  the  present  there  has  not 
been  demonstrated  by  gaseous-exchange  experiments  concordant  results  as 
to  a  quenching  of  the  heat  production  through  the  function  of  the  insular 
apparatus,  other  considerations,  however,  seem  to  ascribe  to  the  pancreas  an 
important  role  in  the  calorie  economy. 

V.  Noorden  first  adhered  to  such  an  opinion,  in  that  he  indicated  the  possi- 
bility "that  fixing  of  glycogen  and  sugar-production  can  be  disturbed,  while 
fat  formation  from  carbohydrate  still  functionates.  The  fat  tissue  then 
takes  up  the  excessively  formed  carbohydrate  (as  fat) ;  there  already  exists  a 


THYROGENIC    OBESITY  573 

true  diabetic  disturbance  of  metabolism,  but  without  glycosuria"  (diabeto- 
genic obesity). 

I  would  consider  in  the  following  consideration  a  further  possibility: 
It  is  known  that  carbohydrates  have  the  ability  to  save  protein  to  a  much 
larger  extent  than  fat,  and  that  an  individual  can  hardly  maintain  his  nutri- 
tion on  protein  and  fat  alone.  An  abundant  feeding,  especially  when  there 
is  a  simultaneous  raising  of  the  protein  constituent,  succeeds  only  when  there 
is  abundant  carbohydrate  in  the  diet.  Hence  carbohydrate  diminishes  the 
decomposition  of  the  protein.  As  the  specific  dynamic  energy  of  protein  is 
very  much  higher  than  that  of  fat  and  of  carbohydrate  the  increase  of  the 
calorie  production  associated  with  the  more  abundant  ingestion  of  nutrition 
is  restricted.  Now  to-day  there  is  not  a  particle  of  doubt  that  the  ac- 
cumulation of  carbohydrates  is  under  the  governing  power  of  the  insular 
apparatus.  There  must  also  accrue  to  the  pancreas  a  direct  influence  on  the 
assimilation  of  fat,  not  only  because  on  the  ingestion  of  abundant  carbo- 
hydrates a  portion  of  these  is  converted  into  fats,  but  because  in  severe  dia- 
betes the  elimination  of  ketone  bodies  increases  enormously  on  the  adminis- 
tration of  abundant  fat.  For  fattening,  therefore,  is  necessary  a  functionally  in- 
tact pancreas.  That  we  so  often  see  diabetes  supervene  in  fat  people  is  per- 
haps due  to  the  fact  that  the  long  overstrained  pancreas  becomes  insufficient, 
apart  from  the  circumstance  that  chronic  overfeeding  is  often  associated 
with  other  factors  deleterious  to  the  pancreas  (alcoholism,  continual  hypere- 
mia of  the  abdominal  organs,  etc.). 

The  considerations  up  to  the  present  are  concerned  chiefly  with  exogenous 
obesity.  We  can  conceive,  however,  that  the  origin  of  obesity  may  receive 
an  impetus  through  a  primarily  strengthened  function  of  the  insular  apparatus, 
in  that  the  assimilation  of  larger  amounts  of  food  goes  on  abnormally  easily, 
and  hence  there  does  not  occur  the  setting  free  of  the  reactions  that  in 
normal  individuals  work  against  an  ingestion  of  food  which  for  a  long  time 
supersedes  the  need. 

2.  Thyrogenic  Obesity 

The  idea  of  thyrogenic  obesity  was  first  set  forth  by  von  Hertoghe,  v. 
Noorden,  Lorand,  Ewald,  and  others.  Occasion  for  it  was  given  by  observations 
of  rather  rapidly  developing  obesity  with  slight  symptoms  of  hypothyrosis, 
slight  pufhness  of  the  face,  apathy,  diminution  of  memory,  insomnia,  etc. 
To  it  is  often  added  a  slight  grade  of  anemia.  Such  individuals  often  bear 
reducing  treatment  very  badly,  v.  Noorden  mentions  especially  that  in  such 
cases  reducing  treatment  often  leads  to  conditions  of  cardiac  weakness,  while 
a  thyroid-gland  treatment  is  often  accompanied  by  rapid  results,  the  manifold 
oppressive  symptoms  disappear,  the  individuals  become  livelier,  fresher,  and, 
although  they  eat  with  appetite  and  do  not  essentially  restrict  the  intake  of 
food,  they  now  gain  in  weight  rapidly.     There  appear  to  be  very  dift'erent 


574  OBESITY    AXD    ADIPOSITAS    DOLOROSA 

etiological  factors  that  lead  to  such  a  slight  functional  disturbance  of  the 
thyroid  gland.  In  many  cases  there  had  been  numerous  parturitions  fol- 
lowing each  other  at  short  intervals.  In  others  the  obesity  develops  imme- 
diately at  the  close  of  a  protracted  infectious  disease,  v.  Xoorden  mentions 
for  instance  cases  in  which  the  obesity  developed  progressively  after  an 
abdominal  typhoid,  and  refers  to  similar  examples  from  the  French  literature. 
The  diagnosis  of  this  form  of  obesity  is  often  difficult,  because  the  symp- 
toms of  hypothyrosis  are  only  suggested.  The  justification  for  one's  regard- 
ing the  hypothyroidism  as  the  cause  of  the  obesity  can,  however,  in  many 
such  cases,  indeed  not  be  doubted.  It  is  found  in  the  entire  course  of  the  dis- 
ease and  in  the  excellent  action  of  the  thyroid  treatment,  which  wx  may  re- 
gard as  a  sort  of  functional  test.  Of  course  thyroid  gland  acts  as  an  agent 
that  reduces  weight  also  in  the  cases  of  ordinary  exogenous  obesity.  The 
essential  point  lies,  however,  as  v.  Xoorden  mentions,  in  the  difference  between 
the  complete  action  of  the  thyroid  cure  and  the  intolerance  against  much 
withdrawal  of  food,  and,  as  I  would  attach  especial  value  to,  in  the  high 
tolerance  for  thyroid-gland  preparations.  From  the  theoretical  standpoint 
the  assumption  of  such  a  thyrogenic  obesity  is  well  founded.  We  can  con- 
ceive that  just  in  such  slight  degrees  of  thyroid-gland  insufficiency,  the  bal- 
ance between  thyroid-gland  function  and  the  function  of  the  pancreas  is  dis- 
turbed in  favor  of  the  latter,  and  that  thus  is  furnished  the  impulse  for  the 
origin  of  an  obesity,  while  with  a  severe  disturbance  of  the  function  of  the 
thyroid  often  all  vegetative  functions  are  highly  diminished,  and  therewith 
the  ingestion  of  food  and  the  appetite  are  restricted.  The  very  general 
observation  that  in  such  cases  of  thyrogenic  obesity  the  assimilation  limits 
for  carbohydrates  lie  abnormally  high,  indicates  with  the  greatest  probability 
a  preponderance  of  the  pancreatic  function. 

3.  Dystrophia  Adipose -genitalis 

In  this  form,  whether  it  be  of  primary  genital  or  hypophysial  origin,  there 
is  found  a  characteristic  distribution  of  fat  such  as  has  been  described  in  detail 
in  the  corresponding  chapters.  It  depends  on  the  withdrawal  or  the  weaken- 
ing of  the  protective  influence  of  the  interstitial  glands  on  body  formation. 
The  distribution  of  fat  has  per  se  nothing  to  do  with  obesity,  as  it  is  re- 
tained in  such  individuals  when  they  otherwise  become  very  thin  on  any 
other  basis,  and  for  the  reason  that  sure  cases  of  hypophysial  dystrophy  and 
also  many  eunuchoids  do  not  come  to  the  development  of  a  pronounced  obes- 
ity, w^hile  the  abnormal  distribution  of  fat  is  always  present.  Also  a  certain 
degree  of  fatty  infiltration  of  the  muscles  may  be  peculiar  to  this  dystrophy, 
independently  of  obesity,  as  well  as  a  weak,  velvety  texture  of  the  skin,  and 
the  behavior  of  the  hair.  The  fact  is,  however,  that  in  both  forms,  obesity 
develops  very  commonly,  even  to  excessive  degree.     The  factors  that  give 


ADIPOSITAS    DOLOROSA  575 

occasion  to  this  are  as  yet  not  entirely  clear.  We  must  consider  that  eu- 
nuchoids have  another  temperament  than  normal  individuals;  they  are  less 
lively,  have  less  energy,  the  muscular  tonus  is  slighter;  in  h}-pophysial  dys- 
trophy there  also  happens  that  in  the  severer  cases  the  vegetative  functions 
seem  to  course  more  slowly,  and  the  fundamental  exchange  therefore  is 
established  at  a  low  level,  as  experimental  investigations  on  animals  have 
shown.  Also  in  these  forms  the  function  of  the  insular  apparatus  seems 
to  have  a  certain  preponderance,  at  least,  as  has  already  been  set  forth  in 
detail,  in  almost  all  cases  there  is  a  strikingly  high  tolerance  for  carbohy- 
drates. In  the  intimate  pathological  correlations  between  glandular  h^-po- 
physis  and  thyroid,  also  a  thyrogenic  factor  can.  in  many  cases  of  hypo- 
physial dystrophy,  very  well  play  a  part.  Ordinarily  this  does  not  seem  the 
case,  at  least  the  result  of  a  thyroid  treatment  in  such  cases  is  not  so  excel- 
lent as  in  the  ordinary  obese  individuals,  and  the  tolerance  for  the  admin- 
istration of  thyroid  gland  is  not  essentially  higher.  There  are  numerous 
statements  in  the  literature  that  in  such  cases  of  hA-pophysial  dystrophy 
the  peroral  administration  of  hypophysis  tablets  or  eventually  a  combina- 
tion [of  these]  with  sexual  gland  substance  was  followed  by  results. 

4.  Epiphysial  Obesity 

It  is  as  yet  doubtful  whether  we  are  justified  in  recognizing  such  a  form. 
At  all  events  it  is  remarkable  that  commonly  with  the  development  of  pineal 
tumors  in  adults,  obesity  also  develops.  This  may  attain  an  excessive 
degree.  We  may  readily  conceive  that  the  obesity  may  be  brought  about 
on  account  of  limitation  of  function  of  the  neighboring  h^-pophysis.  Actu- 
ally, in  the  case  of  Raymond  and  Claude,  the  hypophysis  was  very  much 
flattened.  One  would  then  expect  the  other  characteristic  symptoms  of 
hypophysial  dystrophy  in  all  cases.  From  the  cases  in  the  Uterature,  which, 
however,  have  not  been  described  very  exactly.  I  have  not  succeeded  in 
eliciting  a  safe  basis  for  this. 

B.  ADIPOSITAS  DOLOROSA 

In  the  years  1882  and  1892  respectively.  Dcrcum  described  a  disease 
picture  which  is  characterized  by  the  peculiar  form  of  fattening  and  by  the 
painfulness  of  the  fat  masses.  Later  Vitaut  called  attention  to  two  additional 
cardinal  symptoms,  namely  the  asthenia  and  certain  psychical  alterations. 
Dercum  considered  the  disease  as  due  to  an  especial  form  of  dysthroidia;  since 
that  time  numerous  appropriate  cases  have  been  reported;  most  authors 
adhere  to  the  ductless  glandular  pathogenesis  of  this  disease,  although  others, 
especially  French  authors,  oppose  the  setting  up  of  this  syndrome  as  a 
disease  sui  generis,  advocating  the  opinion  that  from  this  syndrome  there 


576 


OBESITY    AND    ADIPOSITAS    DOLOROSA 


are  transitions  to  the  different  forms  of  lipomatosis  and  to  the  trophic  edemas. 
Lately  Lyon  is  even  of  the  opinion  that  also  the  different  forms  of  obesity 
and  those  of  lipomatosis  go  over  into  each  other  without  sharp  boundaries. 
Many  authors  assume  a  nervous  trophic  origin  for  this  syndrome.  Before 
I  enter  into  the  description  of  the  syndrome,  I  would  like  to  report  an  appro- 
priate case. 

Observation  LXX. — Fr.  B.,  fifty-six  years  old.  Entered  the  first  medical  clinic  Sept.  3, 
1912.  The  parents  of  the  patient  were  both  corpulent.  Of  five  brothers  three  are  very 
corpulent,  and  of  four  sisters,  two.     According  to  the  statement  of  the  son  the  localization 


Fig.  96. —  Case  of  adipositas  dolorosa  (Observation  LXX). 


of  the  fat  in  the  corpulent  relatives  is  not  just  the  same  as  in  the  patient.  The  four  chil- 
dren are  not  adipose.  There  is  no  diabetes  or  gout  in  the  family,  so  far  as  is  known.  As 
a  child  and  youth  the  patient  was  healthy.  The  obesity  began  to  develop  during  his  mili- 
tary service,  especially  later,  however,  when  the  patient  adopted  a  sedentary  life;  he  was 
landlord  of  an  inn  and  ate  and  drank  very  much,  consuming  4.}^  liters  of  wine  daily  and 
smoking  very  much.  The  obesity  was  especially  heavy  from  the  thirty-fifth  year  of  life 
on.  The  fat  developed  in  cushions  on  the  shoulders,  on  the  upper  arm,  on  the  thorax,  and 
on  the  pelvic  girdle,  while  forearms  and  hands  and  [lower]  legs  and  feet  remained  thin. 
For  about  ten  years  there  often  occurred  oppressions  of  respiration  and  vertigo,  especially 
on  going  up  stairs  and  on  long  marches.  Lately  he  can  hardly  walk  on  this  account.  The 
appetite  became  slight,  and  he  ingests  practically  only  liquid  nutrition.  In  the  spring  of 
191 2  he  weighed  as  much  as  140  kg.  Since  that  time  he  lost  about  30  kg.  For  a  long  time 
there  has  existed  pains  in  the  hepatic  region;  during  the  last  weeks  he  vomited  several 
times  daily,  independently  of  the  ingestion  of  food,  also  belches.     For  the  last  year  there 


ADIPOSITAS   DOLOROSA 


577 


has  been  entire  impotence  and  failure  of  libido  which  for  a  long  time  has  been  developed 
only  very  moderately. 

The  patient  now  weighs  105  kg.  and  by  Nov.  9  had  lost  3  kg.  more.  The  body  length  is 
170  cm.,  the  span  width,  169  cm.,  the  greatest  circumference  of  the  abdomen,  124  cm. 
There  are  enormous  accumiilations  of  fat  on  the  upper  arms  and  on  the  outer  sides  of  the 
shoulders,  also  on  the  inner  side  of  the  upper  arm,  also  a  thick  cushion  of  fat  over  the  verte- 
bra prominens  (a  true  fat  neck),  also  on  the  outer  sides  of  the  buttocks  and  of  the  thighs; 
the  thin  forearms  and  [lower]  legs  stand  in  characteristic  contrast  to  the  heavy  fat  accu- 
mulations on  the  shoulder  and  pelvic  girdle.  In  consequence  of  these  the  patient  presents 
the  appearance  of  an  athlete.  On  closer  examination,  however,  it  is  noted  that  the  body 
build  is  slender,  and  that  thorax  and  pelvic  girdle  are  not  abnormally  broad.  The  cir- 
cumference about  the  shoulders  is,  in  consequence  of  the  enormous  cushions  of  fat,  128  cm. 


Fig.  97. — Inflammatory  alteration  of  the  feet-tissue  in  a  case  of  adipositas  dolorosa 

(Observation  LXX). 


The  circumference  of  the  abdomen  a  hand's  breadth  under  the  xiphoid  process  is  122  cm., 
the  greatest  circumference  of  the  thorax,  123  cm.,  the  greatest  circumference  of  the  upper 
arm  on  both  sides,  40  cm.  On  the  inner  side  of  the  forearm  may  be  felt  on  both  sides  sev- 
eral symmetrical  fat  nodules,  the  size  of  a  nut;  the  fat  has  accumulated  more  abundantly 
on  the  upper  part  of  the  thorax,  in  the  vicinity  of  the  nipples,  so  that  it  drapes  forward 
in  two  enormous  folds,  directed  obliquely  outward  and  downward,  and  drapes  backward 
in  several  oblique  and  horizontal  folds.  From  the  waist  on  the  fat  again  begins  to  be 
enormous,  so  that  it  hangs  below  like  an  apron  over  the  symphysis  and  half  conceals  the 
genitalia. 

Also  laterally  over  both  iliac  bones  are  enormous  fat  nodules  that  are  bounded  below 
37 


578 


OBESITY    AND    ADIPOSITAS    DOLOROSA 


by  folds.  On  the  outer  side  of  the  femur  palpation  reveals  a  more  diffuse  embedding  of 
dense  nodular  fat.  On  the  inner  side  is  found  on  each  side  an  enormous  fat  nodule. 
The  distribution  of  fat  is  everywhere  strictly  symmetrical.  At  some  places  are  found  thick 
symmetrically  disposed  fat  nodules  of  the  size  of  a  hen's  egg  to  that  of  an  apple.  Often 
the  nodules  are  smaller,  seeming  to  the  palpating  finger  like  small  nodules.  Everywhere 
over  the  fat  cushions  are  to  be  seen  ectatic  veins,  around  which  are  plainly  evident  in  the 


U^!^^" 


^ 


\^^'  ■ 


•-aq;j-_--_^ 


&kk        ■\'^ 


Fig.  98. — Thyroid  in  a  case  of  adipositas  dolorosa  (Observation  LXX). 


whole  course  of  the  veins  fat  disposed  like  bunches  of  grapes.  Here  the  fat  is  especially 
painful. 

The  left  lobe  of  the  thyroid  gland  shows  a  struma  about  the  size  of  a  goose  egg. 

The  border  of  the  liver  is  palpable  three  finger-breadths  below  the  border  of  the  ribs, 
and  is  hard.     The  urine  shows  urobilin  and  traces  of  albumin. 

Test  as  to  alimentary  glycosuria  (100  gm.  dextrose)  negative. 


ADIPOSITAS    DOLOROSA  579 

After  injection  of  3  c.c.  pituitrinum  glandulare,  andlater  5  c.c,  there  was  no  increase 
of  temperature. 

The  blood  sugar-contents  is  normal. 
Blood  count:  Leucocytes,  12,000,  of  which: 
Neutrophiles,  50  per  cent. 
Lymphocytes,  42  per  cent. 

m^^^'^^'^'./^- --'''. ~-fY-  '^.'^  c;  »^-  ^'^^ci^rA^  ,-:'    .   "a  '•;       ^.^''■' 


^fc-^:^^:  V':^=i^;.%,/'  'V^.r^^':v-  ''%:^-^,^.:C^ 

Fig.  99. — Hypophysis  in  a  case  of  adipositas  dolorosa. 

Large  mononuclears,  6  per  cent. 
Eosinophiles,  2  per  cent. 

X-ray  shows  that  the  aorta  is  7  cm.,  the  heart  13.5  cm.  broad.     The  genitals  show 
nothing  especial. 

The  sella  turcica  is  seen  (by  X-ray)  to  be  of  normal  size. 

Nerve  status:  The  fundus  is  normal.  The  pupils  react  promptly.  Patellar  reflexes 
are  weak  on  both  sides,  superficial  abdominal  and  cremasteric  reflexes  normal.  No 
Babinski,  no  Romberg.  Slight  paresis  of  the  right  facial  nerve.  Distinct  alcoholic 
tremor.  Gross  strength  of  the  muscles  reduced.  Gait  somewhat  insecure.  Sensibility 
not  essentially  disturbed. 

The  microscopical  examination  of  an  excised  piece  of  fat  showed  pronounced  peri- 


580  OBESITY    AND    ADIPOSITAS    DOLOROSA 

vascular  infiltration  consisting  especially  of  mononuclear,  and  partially  of  polynuclear 
cells.  Especially  distinct  is  this  infiltration  in  the  interstitial  connective  tissue  between 
the  individual  fat  lobules,  although  the  smallest  perivascular  infiltrations  are  found  also 
around  the  capillaries  between  the  fat  cells  themselves. 

The  patient  went  down  very  rapidly,  soon  he  was  not  oriented  any  more  as  to  time  and 
space;  there  occurred  hallucinations  of  faces,  he  spoke  confusedly,  believed  himself  to  be 
on  a  journey,  whistled  and  made  a  noise,  especially  at  night.  Apparently  there  was  diplo- 
pia on  looking  toward  the  left.  Slight  paresis  of  the  left  abducens.  The  ingestion  of 
food  became  always  slighter;  nutritive  enemas  were  not  retained.  At  times  vomiting. 
The  pulse  accelerated,  small,  soft  cardiac  remedies  were  without  effect.  At  the  close  there 
developed  an  ulcerous  pharyngitis,  later  bronchitic  murmurs;  death  occurred  with  in- 
creased cardiac  weakness. 

Autopsy  (Assistant  Dr.  Schopper).  Hypertrophic  cirrhosis  of  the  liver  with  moderate 
enlargement  of  the  organ  and  uniformly  granulated  superficial  and  cut  surface.     jMarked 


Fig.   100. — Anterior  lobe  of  hypophysis  in  a  case  of  adipositus  dolorosa  (Observation  LXX). 

fat  infiltration  of  the  heart  in  the  form  of  nodular  fat  lobules  with  penetration  of  the  fat 
until  up  to  the  endocardium.  Concretio  cardio  cum  pericardio.  Increase  of  the  fat  also 
in  the  pericardium,  hypostasis  of  the  lungs,  etc.  Chronic  internal  hydrocephalus  with 
granular  thickening  of  the  ependyma.  Slight  fatty  degeneration  of  the  kidneys  and  of 
the  myocardium.  Acute  splenic  tumor.  Ulcerative  pharyngitis.  Marked  atheromatosis 
of  the  aorta.     Slight  sclerosis  of  the  peripheral  arteries. 

The  distribution  of  fat  corresponds  to  the  clinical  description.  The  fat  is  of  a  yellow- 
ish gray  color,  firm  consistence  with  individual  stripes  and  spots  of  white-gray  color  that 
are  appreciable  even  macroscopically. 

The  hypophysis  is  rather  small,  otherwise  macroscopically  normal. 

The  thyroid  gland  is  macroscopically  for  greatest  part  quite  normal,  in  the  left  lobe  is 
found  a  goose-egg-sized  strumous  nodule. 


ADIPOSITAS    DOLOROSA 


581 


The  suprarenals  are  microscopically  normal. 

Also  in  the  sexual  glands  is  found  nothing  especial.  The  pancreas  is  macroscopically 
normal. 

The  microscopical  examination  of  the  pancreas  and  the  suprarenals  showed  fvdly  nor- 
mal conditions.  The  microscopical  examination  of  the  thyroid  gland  showed,  as  the 
adjoining  illustration  shows,  a  colloid  struma,  yet  there  is  stUl  found  everywhere  abundant 
thyroid  glandular  tissue  of  normal  consistency  (Fig.  98). 

Also  the  microscopical  examination  of  the  hypophysis  showed  normal  relations,  as  well 
in  the  glandular  lobe  as  in  the  nervous  lobe  and  in  the  pars  intermedia. 


^^^-^ 


Fig.  ioi. — Perivascular  infiltration  in  a  case  of  adipositas  dolorosa  (Observation  LXX). 

Fig.  99  shows  a  general  view.  ■ 

Fig.  100  shows  a  portion  of  the  glandular  part  on  higher  magnification. 

Also  another  piece  of  fat  tissue  was  examined  microscopically;  in  this 
section  there  was  a  perivascular  infiltration,  more  distincth'  developed  about 
the  large  vessels.     See  Fig.  loi. 

S3miptomatology.- — Adipositas  dolorosa  or  adiposis  dolorosa  is  found  more 
commonly  in  women  than  in  men.  It  usually  begins  between  the  forty-hfth 
and  the  sixtieth  years  of  life.  In  women  the  disease  often  sets  in  with 
the  menopause.  There  are,  however,  individual  cases  in  which  the  beginning 
occurred  at  the  eleventh  year  of  life.  As  cardinal  symptoms  of  the  disease 
are  regarded  the  fat  tumors,  the  tenderness  of  the  fat  to  pressure  or  its  pain- 
fulness  spontaneously  (Dercum),  the  asthenic  and  the  psychical  alterations 


582  OBESITY    AND    ADIPOSITAS    DOLOROSA 

(Vitaut).  In  addition  there  have  been  described,  however,  a  series  of  ac- 
cessory symptoms,  that  consist  especially  in  disturbances  on  the  part  of  the 
motor,  sensory,  and  vegetative  nerves. 

The  distribution  of  the  fat  tumors  may  vary.     Vitaut  first  distinguished: 

(a)  Nodular,  asymmetrical  fat  tumors,  disposed  asymmetrically  in  and 
under  the  skin — lipomatose  nodulaire. 

(b)  Circumscribed,  diffuse,  not  sharply  delimitable  fat  growths,  lipo- 
matose diffuse  localisee. 

(c)  General  diffuse  fat  growths,  lipomatose  diffuse  generale;  this  is  the 
most  frequent  form,  and  in  it  the  fat  is  not  uniformly  distributed  as  in  ordi- 
nary adiposity,  the  skin  shows  much  more  an  uneven  texture.  The  fat 
masses  feel  lump-like,  like  a  bundle  of  worms  (Dercum),  and  at  those  places 
especially  where  a  pressure  is  exerted,  for  instance  in  the  waist,  or  where  the 
garters  press,  they  are  separated  from  each  other  by  deep  furrows. 

In  lipomatose  diffuse  localisee  the  accumulations  of  fat  are  mostly  found 
only  on  the  trunk  and  on  the  proximal  third  of  the  extremities.  In  such 
cases  the  fat  deposits  may  be  quite  excessive  and  hang  down  like  an  apron, 
as  for  instance  in  a  case  of  Dercum  and  McCarthy's,  in  which  the  fat  masses 
hung  laterally  over  the  hips  and  backward  over  the  buttocks  in  thick  folds, 
or  in  a  case  of  Lbning  and  Fuss's  in  which  the  fat  masses  hung  from  the  abdo- 
men and  the  inguinal  region  almost  to  the  lower  third  of  the  thigh. 

In  the  nodular  form  the  throat  and  face,  as  well  as  hands  and  feet,  eventu- 
ally also  the  forearms  and  [lower]  legs  are  entirely  free;  the  latter  are 
often  very  thin.  In  a  case  of  Debove's  there  was  found,  especially  on  the 
outer  side  of  the  upper  arm,  symmetrically  disposed  masses  up  to  the  size 
of  a  pigeon's  egg.  The  hands  were  entirely  free.  These  fat  nodules  may 
be  arranged  in  a  multiple  manner,  or  symmetrically. 

On  careful  observation  of  the  reported  cases  we  may  see  that  all  transi- 
tions between  these  three  types  occur.  This  was  already  observed  by 
Weiss;  the  classification  has  but  little  value.  I  refer  to  the  case  detailed 
above,  which  constitutes  a  combination  of  lipomatosis  nodulaire  and  lipo- 
matosis diffuse  localisee. 

The  second  cardinal  symptom  consists  in  the  painfulness  of  the  fat. 
In  many  cases  there  is  a  sensation  of  violent  burning  "as  if  a  dog  were  tear- 
ing the  flesh  from  the  body"  (Haskovec);  in  other  cases  the  pains  occur  in 
attacks,  under  circumstances  before  the  fat  infiltrates  become  visible.  In 
other  cases  vesicles  appear  during  the  attacks  of  pain.  In  other  cases  spon- 
taneous pains  are  absent,  the  fat  infiltrates  are  painful  only  on  pressure;  in 
my  case  the  painfulness  of  the  fat  infiltrate  was  bound  chiefly  to  the  vicinity 
of  the  dilated  veins.  There  are  also  cases  described,  otherwise  typical, 
in  which  the  tenderness  to  pressure  was  but  very  slight. 

In  all  cases  the  asthenia  is  more  or  less  distinctly  pronounced.     In  the  case 


ADIPOSITAS    DOLOROSA  583 

described  above,  the  muscular  weakness  was  so  great  that  the  patient  could 
scarcely  walk. 

Psychical  alterations  are  indeed  very  common,  but  not  constant.  The 
case  of  Ldning  and  Fuss,  a  sixty-six-year-old  woman  in  whom  the  disease  had 
existed  for  about  twelve  years  was  mentally  entirely  normal  and  active.  The 
psychical  alterations  are  very  various.  In  many  cases  hallucinations  and 
conditions  of  excitement  are  observed,  in  others,  as  for  instance  Ballefs  case, 
depressive  melancholic  conditions.  Also  the  accessory  symptoms  are  very 
diverse  and  not  constant.  On  the  part  of  the  motor  nerves  are  observed 
tremor  (alcoholism),  slowing  of  the  speech,  alterations  of  the  reflexes,  es- 
pecially reduction.  On  the  part  of  the  sensory  nerves  there  are  hyper- 
esthesias and  paresthesias,  disturbances  of  the  sensibility,  etc.,  on  the  part 
of  the  vegetative  nerves  often  vasomotor  symptoms  such  as  dermographism, 
tachycardia,  dyspnea,  anidrosis,  and  hyperidrosis.  There  occurs  in  addition, 
trophic  disturbances,  such  as  premature  turning  gray  of  the  hair,  and  on  the 
part  of  the  vascular  system  hemorrhages,  inclination  to  nose-bleed,  purpura, 
etc.  As  may  be  seen,  very  diverse  symptoms  are  collected  together  in  this 
group.  As  we  are  mostly  dealing  with  elderly  people  with  fatty  heart  and 
severe  alcoholism,  many  of  these  symptoms  are  readily  intelligible  wdthout 
anything  further. 

Investigations  as  to  the  metabolism  are  as  yet  very  sparse.  Schwenck- 
enhecher  observed  two  cases  in  which  the  body  weight  only  began  to  fall 
when  the  administration  of  calories  was  as  low  as  19  calories  per  kilogram. 
In  many  cases  polydipsia  is  asserted,  in  others  reduction  of  the  body 
temperature. 

Pathological  Anatomy. — There  are  already  a  series  of  autopsies,  into  a 
consideration  of  which  I  shall  enter  somewhat  exactly,  as  it  is  necessary  for 
the  discussion  of  the  pathogenesis. 

Dercum  described  two  cases,  in  which  were  found  macroscopically  en- 
largement and  calcareous  infiltration  of  the  thyroid  gland.  In  a  case  of 
Dercum's  was  found  uniform  atrophy  of  the  thyroid  gland,  and  widespread 
interstitial  neuritis  of  the  peripheral  nerves  in  the  depositions  of  fat.  In  a 
case  of  Burr's  was  found  degenerative  alterations  in  many  lobules  of  the  thy- 
roid gland,  also  a  ghoma  of  the  h^^ophysis,  and  in  addition  interstitial 
neuritis,  sclerosis  of  the  liver,  and  atrophy  of  the  ovaries.  In  a  case  of  Dercum 
and  McCarthys  the  thyroid  gland  was  normal,  there  was  found  an  adeno- 
carcinoma of  the  hypophysis,  enlargement  of  the  right  suprarenal,  hemo- 
lymph  glands  in  the  fat  tissue,  interstitial  neuritis,  hypoplasia  of  the 
testicles,  and  acute  parenchymatous  nephritis.  In  a  case  of  Guillain  and 
Alguier's  the  thyroid  gland  was  found  to  be  enlarged  and  the  connective  tissue 
in  it  increased.  The  hypophysis  was  likewise  enlarged,  the  connective  tissue 
in  the  glandular  portion  was  increased,  in  association  with  which  the  eosino- 
philic and  basophilic  cells  were  increased,  alterations  that  reminded  both 


584  OBESITY   AND   ADIPOSITAS   DOLOROSA 

these  authors  of  an  alveolar  carcinoma.  In  a  case  of  Price's  there  were 
found  inflammatory  alterations  in  the  thyroid  gland  as  well  as  in  the  hypo- 
physis (alveolar  or  glandular  carcinoma?)  and  interstitial  neuritis.  In  a 
second  case  there  was  found  in  the  thyroid  gland  much  interstitial  tissue, 
the  acini  were  dilated,  the  hypophysis  showed  similar  but  not  essential  al- 
terations. In  the  fat  tissue  no  especial  alterations  were  found.  In  a  case  of 
Loning  di.ndFuss's  the  thyroid  gland  was  dense,  changed  into  a  whitish-yellow 
callous  tissue;  microscopically  was  found  smallness  of  the  gland  cells  and 
round-cell  infiltrate,  the  h>'pophysis  was  small,  soft,  unaltered.  Finally, 
in  my  case  there  were  no  essential  alterations  in  the  ductless  glands.  We 
can  hardly  ascribe  any  especial  significance  to  the  colloid  struma,  there 
were  found  perivascular  infiltrates  in  the  fat  tissue,  and  cirrhosis  of  the 
liver. 

Summing  up  the  autopsy  findings  we  find  the  following:  Among  eleven 
cases,  there  were  found  nine  times  alterations  of  the  thyroid  gland,  especially 
of  a  chronic  inflammatory  nature.  The  hypophysis  was  examined  micro- 
scopically in  seven  cases.  Among  these  were  found  alterations  five  times, 
and  these  indeed  of  a  very  diverse  nature  (round-cell  infiltration,  sclerosis, 
adenocarcinoma,  glioma).  Also  in  the  sexual  glands  was  sometimes  found 
sclerosis,  in  addition  to  which  was  found  ovarian  cysts,  and  once  hypoplasia 
of  the  testicles.  Liver  and  spleen  often  show  cirrhotic  changes,  the  kidneys 
sometirnes  interstitial  changes.  The  microscopical  examination  of  the 
fat  often  showed,  as  well  in  the  diffusely  distributed  fat  as  in  the  encapsu- 
lated lipomata,  abundant  connective  tissue;  and  in  some  cases  newly  formed 
hemolymph  nodules  or  perivascular  inflammatory  infiltration.  In  other 
cases  there  were  found  no  inflammatory  alterations.  Very  frequently,  there 
was  found  interstitial  neuritis  (six  times  among  seven  cases  investigated) ,  as 
well  in  the  fine  nerve  trunks  in  the  fat  tissue  itself,  as  in  the  nerves  of  the 
muscles.     In  one  case  there  was  degeneration  of  GolVs  column. 

Pathogenesis. — The  views  of  the  authors  as  to  the  pathogenesis  of 
adipositas  dolorosa  are  very  different.  Dercum  considered  the  cause  of 
the  affection  as  a  sort  of  dysthyroidia,  through  which  came  about  a  re- 
duction of  fat  combustion  and  inflammatory  alterations  of  the  nerves. 
Vitaut  expresses  himself  similarly.  Most  of  the  authors  assume  a  chronic 
intoxication,  the  cause  of  which  they  see  in  a  disturbance  of  the  function  of 
the  ductless  glands  {Price,  Ballet,  Miguel);  but  they  are  not  agreed  as  to 
which  ductless  gland  is  at  fault.  For  example.  Price  beheves  that  in  addi- 
tion to  the  thyroid,  the  hypophysis  plays  an  especial  part.  Ballet  regards 
the  involvement  of  the  thyroid  gland  as  unlikely  and  thinks  of  disturbances 
of  the  other  ductless  glands,  etc.  Debove  places  the  nervous  system  as 
the  central  figure  of  the  pathogenesis.  Struhing  and  Thimm  regard  the 
disease  as  a  trophoneurosis,  Haskovcc  as  a  central  trophoneurosis.  Sicard 
and  Rousskv  think  of  an  involvement  of  the  ovarv,  as  thev  saw  the  disease 


ADIPOSITAS   DOLOROSA  585 

develop  after  ovariotomy  in  two  relatively  youthful  cases.  Schwenken- 
hecher  believes  in  an  endogenous  obesity,  with  a  pressure  of  the  fat  growth 
on  the  small  vessels  and  nerves,  causing  circumscribed  circulatory  disturb- 
ances and  paresthesias.  We  thus  see  that  the  views  as  to  the  pathogenesis 
of  this  disease  diverge  greatly. 

Before  I  discuss  the  significance  of  the  ductless  glandular  system  for  this 
disease,  I  would  like  to  say  a  few  words  concerning  the  relationship  of  these 
to  Upomatosis.  The  view  has  been  adopted  by  French  and  German  authors 
that  adiposis  dolorosa  is  no  disease  sui  generis,  but  only  a  syndrome  that 
belongs  to  the  great  group  of  lipomatoses  and  of  trophedema.  To  my 
knowledge,  Kbttnitz  was  the  first  to  point  out  that  in  the  symmetrical  lipo- 
mata  there  frequently  occur  constitutional  symptoms,  such  as  nervous 
symptoms,  rheumatoid  pains,  etc.  He  describes  a  case,  in  which  the  meno- 
pause set  in  prematurely,  and  at  the  time  of  the  failing  menses,  symmetrical 
Hpomata  several  times  developed,  the  eruption  of  which  was  attended  with 
pain  in  the  part  of  the  body  in  question.  Kottnitz  regards  adipositas 
dolorosa  as  a  trophoneurosis  and  believes  that  all  transitions  to  the  painful 
symmetrical  lipomata  occur.  Also  Cheinisse  and  Fulconis  maintain  the  iden- 
tity of  the  two  diseases.  After  Potain  and  Mathieu  had  assumed  transitions 
from  neuropathic  edemas  to  pseudolipomata  and  even  to  true  lipomata, 
especially  Strubing,  and  after  him  Thimm,  advocated  the  view  that  neuro- 
pathic edema  (oedeme  blanc  and  bleu),  multiple  lipomatoses,  symmetrical 
diffuse  Hpomata,  and  finally  the  painful  lipomata  all  belonged  to  a  great 
group  of  diseases  that  "had  at  their  foundation  the  same  basic  process." 
Also  Miquel  sought  to  establish  in  detail  that  the  oedeme  neuropathique  of 
Mathieu,  the  oedeme  segmentaire  of  Debove,  the  chronic  trophedema  of 
Meige  and  the  pseudooedeme  catatonique  of  Dide  formed  with  adipositas 
dolorosa  a  great  group,  the  cause  of  which  was  to  be  sought  in  alterations  of 
the  nervous  system  and  of  the  ductless  glands.  Lately  Lyon  after  a  careful 
compilation  of  the  literature  and  the  addition  of  new  material,  has  advo- 
cated a  similar  view. 

The  view  that  fleeting  transitions  exist  between  painful  symmetrical 
lipomata  and  adiposis  dolorosa  has  received  much  support  from  the  works 
of  the  last  years.  Among  the  circumscribed  lipomata  that  are  often  dis- 
tributed in  great  number  over  the  entire  body  are  those,  as  Launois  and 
Bensaude  point  out,  that  are  painful  to  pressure  and  are  associated  mth 
spontaneous  neuralgiform  pains.  In  the  symmetrical  lipomata  the  consti- 
tutional factor  mostly  comes  still  more  strongly  into  the  foreground.  Here 
are  frequently  found  manifestations  of  asthenia,  also  vasomotor  disturb- 
ances, especially  bluish-red  coloration  of  the  skin  over  the  nodes,  paresthesias, 
even  psychic  disturbances.  Also  in  such  cases  the  hereditary  and  famihal 
element  is  often  well  pronounced.  As  an  example  I  cite  a  case  of  Lyon's 
(case  2).     In  two  sisters  painful  symmetrical  lipomata  set  in  at  the   time 


586  OBESITY    AND    ADIPOSITAS    DOLOROSA 

of  puberty  and  attained  their  full  development  at  maturity.  They  were 
associated  with  rheumatoid  pains,  dysmenorrhea,  and  psychic  impairment. 
According  to  Lyon  there  may  be  also  found  in  such  lipomata  lymph  nodules 
similar  to  those  which  are  found  in  adipositas  dolorosa.  That  in  adipositas 
dolorosa  the  distribution  of  fat  may  be  rigidly  symmetrical  is  shown  by  the 
case  quoted  in  detail  above.  A  quite  similar  distribution  of  fat  was  found  in 
a  case  of  Dercum  and  McCarthy's.  In  my  case,  there  were,  in  addition,  lipo- 
mata up  to  the  size  of  a  goose  egg,  with  a  rigidly  symmetrical  distribution. 
This  type  of  fat  distribution  was  also  present  in  a  case  of  Bochroclfs. 

I  will  not  venture  to  pass  judgment  on  the  question  whether  there  are 
also  transitions  between  lipomatosis  and  trophedema.  I  shall  only  register 
some  important  findings.  In  a  case  of  trophedema,  Striihing  found  on 
microscopical  examination,  no  edema  at  all,  but  only  fat  with  strikingly 
large  fat  cells.  Haskovec  describes  a  case  in  which  there  set  in  at  the  meno- 
pause pains  in  the  back  and  in  the  limbs,  attacks  of  weakness,  and  then 
edema,  which,  recurring  constantly,  closed  with  attacks  of  violent  pains. 
At  the  site  of  the  edema  there  then  gradually  developed  a  painful  hyperplasia 
of  the  subcutaneous  fat  tissue.  Haskovec  regards  this  case  as  a  transition  of 
a  vasomotor  neurosis  or  an  acute  edema  to  a  trophoneurosis.  We  must 
remember,  however,  that  the  acute  edema  usually  shows  quite  another 
localization  from  that  of  the  s}Tnmetrical  lipomata.  Also  combination  of 
adiposis  dolorosa  with  other  diseases  that  are  regarded  as  trophoneuroses, 
for  example,  xanthelasma,  are  known.     Debove  has  described  such  a  case. 

Finally,  as  far  as  the  ductless  glands  are  concerned  in  the  pathogenesis 
of  adiposis  dolorosa,  this  seems  to  me  very  doubtful.  The  pathologico- 
anatomical  alterations  in  the  ductless  glands  are  very  diverse.  As  we  have 
pre\iously  seen,  there  have  been  found  rather  frequently  degenerative 
changes  and  especially  chronic  inflammatory  changes  in  some  of  the  ductless 
glands,  especially  in  the  thyroid  gland  and  in  the  hypophysis.  (The  findings 
of  adenocarcinoma  or  glioma  of  the  hypophysis  might  very  well  be  an  acci- 
dental coincidence). 

These  chronic  inflammatory  alterations  seem  to  me  throughout  not  re- 
markable, as  in  this  disease  we  find  them  otherwise  in  many  organs.  Cir- 
rhotic alterations  in  the  liver  and  spleen,  chronic  inflammations  in  the  nerves, 
etc.,  belong  to  the  commonest  findings,  and  may  in  part  be  explained  by  the 
alcoholism  that  is  present.  Thyrogenic  obesity,  a  mild  form  of  myxedema, 
is  widely  distinguished  in  its  clinical  beha\'ior  from  the  picture  of  adiposis 
dolorosa.  Simultaneous  sclerosis  of  the  thyroid  gland  and  of  the  hypophysis 
leads  to  a  combination  of  myxedema  and  cachexia,  a  disease  picture  that 
has  nothing  to  do  with  adipositas  dolorosa.  There  does  not  appear  to  me 
to  be  any  grounds  for  assuming  the  involvement  of  any  of  the  other  ductless 
glands.  The  assumption  of  Lyon  that  all  forms  of  obesity  and  of  lipomatosis 
have  their  origin  in  a  disturbance  of  correlation  of  the  ductless  glands,  I  can- 


ADDENDUM  587 

not  subscribe  to.  Here  too  many  things  are  thrown  together.  The  sup- 
position of  the  disturbance  of  correlation  of  the  ductless  glands  as  the  cause 
of  a  disease  is,  without  corresponding  pathologico-anatomical  correlate  a 
vague  idea,  which  only  obstructs  a  deeper  penetration  into  the  pathogenesis 
of  such  a  disease.  So  that  there  remains  only  the  supposition  of  a  tropho- 
neurosis, although  I  cannot  conceal  the  fact  that  not  much  has  been  gained 
by  this  assumption. 

There  have  been  described  still  other  trophic  disturbances  of  the  fat  tissue 
of  which  I  shall  here  briefly  refer  to  one  only,  although  probably  it  has  less 
to  do  with  the  ductless  glandular  system  than  adipositas  dolorosa.  Pic  and 
Gardere  first  pointed  out  a  trophic  disturbance  which  Simons  has  lately  desig- 
nated lipodystrophia  progressiva.  It  is  concerned  with  disappearance  of 
the  fat  on  the  face  and  arms,  simultaneously  with  a  gradually  increasing 
adiposity  in  the  region  of  the  buttocks  and  on  the  thigh.  Sensory  and  vaso- 
motor disturbances  are  absent.  The  investigation  of  the  fundamental  ex- 
change in  Simon  s  case  showed  normal  relations. 

In  the  differential  diagnosis  of  adipositas  dolorosa  from  myxedema  we 
should  consider  that  in  the  latter  the  swellings  are  especially  in  the  face; 
from  trophedema  that  this  mostly  sets  in  at  an  early  age,  that  the  edema 
is  mostly  unilateral  and  that  hands,  feet,  forearms  and  [lower]  legs  are 
usually  involved;  from  neurofibromatosis  of  Recklinghausen  that  the  nodules 
in  this  affection  are  much  harder  and  also  smaller,  that  they  are  more 
confluent,  that  they  do  not  avoid  hands  and  feet,  and  that  the  psychic  dis- 
turbances are  more  pronounced,  also  that  there  are  often  marked  pig- 
mentations of  the  skin  (Debove).  The  differential  diagnosis  from  alcoholic 
polyneuritis  in  the  obese,  concerning  which  diagnosis  Umber  and  Schwenken- 
becker  have  written,  is  often  very  difficult,  if  the  characteristic  distribution 
of  fat  is  absent. 

In  the  treatment  of  adipositas  dolorosa  a  great  role  is  played  by  thyroidin. 
In  many  cases  the  results  are  indeed  undoubted,  but  this  does  not  furnish 
evidence  for  the  thyrogenic  nature  of  the  disease.  It  has  been  stated  that 
cases  have  been  cured  by  thyroidin  medication  (Price).  Also  the  psychic 
disturbances  have  retrogressed,  v.  Noorden  has  seen  good  results  from 
systematic  bath-treatments.  X-ray  irradiation  and  iodine  have  been 
recommended. 

Addendum 

The  type  of  obesity  described  by  Anders  under  the  name  adiposis  tuberosa 
simplex  is  apparently  nothing  more  than  a  transitional  stage  between  simple 
diffuse  obesity  and  adipositas  dolorosa.  It  is  doubtful  whether  even  the 
latter  will  long  maintain  its  position  as  a  disease  sui  generis.  It  is  probable 
that  many  of  the  cases  described  under  it  could  very  well  be  classed  under 


588  OBESITY   AND    ADIPOSITAS    DOLOROSA 

the  other  varieties  of  obesity.  In  adipositas  dolorosa  we  have  the  additional 
factor  of  pain,  which  may  very  well  be  explained  as  a  neuritis  of  the  small 
nerve  filaments.  In  many  of  the  histories  there  is  quite  enough  to  account 
for  the  existence  of  such  a  neuritis  and  also  the  mental  changes;  nor  is  the 
asthenia  of  sufficient  importance  to  delimit  this  condition  as  a  pathogenic 
entity,  although  for  clinical  purposes  adiposis  dolorosa  does  constitute  one 
of  the  recognizable  types  of  obesity. 

This  being  the  case,  the  question  as  to  which  ductless  glands  are  at  fault 
in  adiposis  dolorosa  seems  to  me  entirely  misplaced.  We  may  very  well  con- 
ceive that  certain  of  the  cases  might  (just  as  ordinary  obesity)  show  no  changes 
in  the  ductless  glands  at  all,  and  that  others  might  show  changes  in  individual 
glands  or  in  several,  as  in  the  varying  types  of  obesity  in  general.  In  no  case, 
or  perhaps  only  very  rarely,  is  the  condition  to  be  regarded  as  pluriglandular 
in  the  author's  conception  of  the  term,  but  rather  as  a  result  of  a  patho- 
logical or  a  physiological  correlation. 

Price  has  recently  contributed  a  case  that  suggests  to  him  the  possibility 
that,  in  addition  to  the  thyroid  condition,  there  were  some  disturbances  in 
function  of  the  parathyroids — the  woman  showed  alternating,  long  periods 
of  apparent  hypothyroidism  and  h}q)erthyroidism  (without  exophthal- 
mus)  and  in  addition,  during  or  just  before  the  periods  of  hyperthyroidism 
flexor  cramps  of  the  extremities,  especially  of  the  hands  and  the  feet. 
Whether  in  this  case  these  cramps  would  be  considered  a  sign  of  hyperexcita- 
bility  of  the  nerves  such  as  would  presage  tetany,  or  constitute  an  attack  of 
tetany,  cannot  be  decided  from  the  case  report  alone. 

McCarthy  and  Karsner  have  recently  reported  a  case  of  adenocarcinoma 
of  the  thyroid,  with  metastases  to  the  cervical  glands  and  pituitary,  which 
they  regard  as  linking  together  three  of  the  groups  of  pathological  fat — 
adiposis  cerebralis,  symmetrical  adenolipomatosis  (a  predominence  cervicale) 
of  Launois  and  Bensaiide,  and  adiposis  dolorosa.  McCarthy  regards  another 
case  reported  by  him  with  Dercum  as  an  intermediate  type  between  adipo- 
sis dolorosa  and  adenolipomatose  symmetrique  a  predominance  cervicale. 
A  third  case  mentioned  by  McCarthy  in  the  report  was  evidently  a  case  of 
eunuchoidism. 

In  the  treatment  mention  should  be  made  of  the  various  "degrassators" 
that  bring  about  a  reduction  of  the  fat  by  electrical  means,  also  of  hot  steam 
or  electrical  light  baths.  It  is  needless  to  state  that  these  measures  should 
be  employed  in  those  weakened  and  debilitated  individuals  affected  with 
adiposis  dolorosa  only  with  extreme  caution,  if  at  all. 

References 

Anders  {H.  S.).     Adiposis  tuberosa  simplex.     Am.  J.  'SI.  Sc,  iqoS,  CXXXW  325-333. 
Price  (G.  E.).     Clinical  types  of  adiposis  and  lipomatosis.     Report  of  a  case  of  adiposis 


ADDEXDl'iE  589 

dolorosa  presenting  unusual  symptoms.     X.  York  'M.  ]..  A'ol.  C.  Xo.  S.  Aug.  22,  1914.  pp. 

35S~357- 

McCarthy  (D.  J.)  and  Karsner  (H.  T.).  Adenocarcinoma  of  the  thyroid  T\-ith  meta- 
stasis to  the  cer\-ical  glands  and  pituitary,  a  contribution  to  the  pathology- of  abnormal  fat 
formation.     Am.  J.  M.  Sc,  191 2.  CXLIA',  S34-847. 

Dercum  (F.  X.)  and  McCarthy  (D.  J.).  Autopsy  in  a  case  of  adiposis  dolorosa. 
Am.  J.  ]\I.  Sc,  124,  994.  1902. 


LITERATURE 

CHAPTER  I 
GENERAL  PART 

Addison,  Thomas,  On  the  constitutional  and  local  effects  of  disease  of  the  suprarenal 

bodies.     London,  1855. 
Adler,  Zur  Physiologic  und  Pathologie  der  Ovarialfunktion.     Arch.  f.  Gynaek.,  95,  349, 

1912. 
Aschner,  tjber  die  Funktion  der  Hypophyse.     Arch.  f.  d.  ges.  Physiol.,  146,  191 2,  u. 

Zur  Physiologic  des  Zwischenhirns.     Wien.  klin.  Wchenschr.,  191 2,  Nr.  27,  1042. 
Asher  and  Flack,  Die  innere  Sekretion  der  Schilddriise.     Ztschr.  f.  Biol.,  60,  1910. 
Balint,  R.  and  B.  Molnar.  Experimentelle  Untersuchungen  iiber  gegenseitige  Wechsel- 

wirkung  innerer  Sekretionsprodukte.     Berl.  klin.  Wchenschr.,  1911,  289. 
Bauer,  Neuere  Untersuchungen  uber  die  Beziehungen  einiger  Blutdriisen  zu  Erkrank- 

ungen  des  Nervensystems,  etc.     Ztschr.  f.  d.  ges.  Neurol,  u.  Psychiat.,  3,  195, 

1911. 
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1902,  u.  ibid.,  29,  1903. 
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III.  Uber  Chemotaxis.     Ztschr.  f.  klin.  ISIed.,  71. 
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90,  617,  1902. 
Brown-Sequard,  Des  effets  produits  chcz  I'homme  par  des  injections  souscoutanees  d'un 

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Physiol,  norm.  u.  path.,  18S9,  651. 
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1905. 
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590 


GEKERAL   PART  59I 

Curschmann,  In  Handbuch  der  inneren  Medizin  v.  Mohr-Staehelin,  5,  1913.     Verl.  v. 

Springer. 
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307,  1912. 
Dupre  and  Guillain,  Association  des  syndromes  basedowien,  sclerodermique  et  tetanique. 

Bull,  et  mem.  soc.  med.  d.  hop.  de  Par.,  Paris,  45,  1900. 
Dupre  and  Kahn,  Sclerodermie  et  maladie  de  Raynaud  syndrome  polyglandulaire.     Gaz. 

d.  hop.,  1909.  866. 
Egger,  F.,  Fieber  bei  vasomotorischen  Neurosen.     Schweizer  Neurologische  Gesellschaft 

Reference  in  Neurol.  Centralbl.,  30,  1911,  218. 
Elliot,  The  action  of  adrenalin.  J.  Physiol.,  32,  1905. 
Eppinger,  Falta,   and  Rudinger,   Wechselwirkung   der   Drlisen   mit   innerer   Sekretion. 

I.  Mittlg.  Ztschr.  f.  klin.  Med.,  66,  1908. 
Eppinger  and  Hess,  Zur  Pathologie  des  vegetativen  Nervensystems  I.     Ztschr.  f.  klin. 

Med.,  67. 
Erdheim,  Hypophysengangsgeschwiilste.     Sitzungsb.  d.  k.  Akad.  d.  Wissensch.     Math.- 

naturw.  CI.  Wien.  Abt.,  Ill,  113,  1904. 
Ewald,   Die   Erkrankungen   der   Schilddrlise,   etc.     Nothnagel,   II   Auflage  Leipzig   u. 

Wien,  1909.     Holder. 
Falta,  W.,  Spateunuchoidismus  und  multiple  Blutdriisensklerose.     Berl.  klin.  Wchenschr., 

1912,  Nr.  30  u.  31. 

—  Tiber  die  Gesetze  der  Zuckerausscheidung,  beim  Diabetes  mellitus.     X.  Mitteilung 

(Theorie).     Ztschr.  f.  klin.  Med.  Berl.,  66,  1908. 

—  Die  Krankheiten  der  Driisen  mit  innerer  Sekretion.     Handbuch  der  inneren  Med. 

von  Mohr-Staehelin,  IV,  1913. 
Falta,  Newburgh,  and  Nobel,  Wechselwirkung  der  Driisen  mit  innerer  Sekretion,  IV, 

tJberfunktion  und  Konstitution.     Ztschr.  f.  klin.  Med.  Berl.,  72,  191 1. 
Falta  and  Priestley,  Beitrage  zur  Regulation  von  Blutdruck-  und  Kohlehydratstoffwechsel 

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V.  Frankl-Hochwart,  Die   Diagnostik  der  Hypophysentumoren  ohne  Akromegalie.     16. 

International  med.  Kongress,- Budapest,   1909.     tjber  den  Einfluss  der  inneren 

Sekretion  auf  die  Psyche.     Med.  klin.,  191 2,  Nr.  48.     Zur  Diagnostik  der  Zirbel- 

driisentumoren.     Deutsche  Ztschr.  f.  Nervenheilk.,  37,  1909. 
Frohlich,  A.,  Tumor  der  Hypophyse  ohne  Akromegalie.     Wien.  klin.  Rundschau.,  1901, 

Nr.  47,  48. 
Gley,  Des  effects  de  I'extirpation  des  glandules  parathyreoides  chez  le  chien  et  le  lapin. 

Arch.  de.  Physiol,  norm,  et  path.,  1897,  18. 
Gougerot,  Syndromes  pluriglandulaires.     Paris  med.,  24  Juin,  1911. 
Grasset,  Traite  elementaire  de  physio-pathologique,  i,  629,  1910. 
Grasset,  see  Cassirer. 
Gull,  A.,  A  cretinoid  state  supervening  in  adult  life  in  women.     Tr.  Clin.  Soc.  Lond., 

7,  180,  1874  and  Brit.  M.  J.,  Nov.,  1873. 
Hedinger,  tJber  Beziehungen  zwischen  Status  lymphaticus  und   Morb.  Add.  Deutsche 

path.  Gesellsch.,  Dresden,  1907. 
Hectoen,  Ein  Fall  von  Sklerodermie  diff .  in  Verbindung  mit  chronisch-fibrosen  Verander- 

ungen  der  Schilddrlise,  etc.     Centralbl.  f.  allg.  Path.  u.  path.  Anat.,  1897,  Nr.  17. 
Hess  and  Konigstein,  tJber  Neurosen  der  Hautgefasse.     Wien.  klin.  Wchenschr.,  Nr.  42, 

1911. 
His,    W.,    Geschichitliches   und   Diathesen   in   der   inneren   Medizin.     Referat.    Kongr. 

f.  inn.  Med.,  191 1. 


592  LITERATURE 

Horsley,  Die  Funktion  der  Schilddriise,  etc.,  Festschr.  f.  \'irchow,  i,  Berlin,  1891. 
Jeandelize,  Insuffisance  thyreoidienne  et  parathyreoidienne.     These  de  Nancy,  1902. 
Jeaiiselme,  Sur  la  coexistance  du  goitre  exophth.  et  de  la  sclerodermic.     Mercredi  med., 

I,  1895. 
Kaufmann,  M.,  tJber  hysterisches  Fieber.     Ztschr.  f.  Neurol,  u.  Psychiat.,  5,  706,  191 1. 

Nervensystem  and  Stoffwechsel.     Handb.  d.  Neurol.,  i,  11 57. 
Kepinow,  Uber  Synergismus  von  Hypophysenextrakt  und  Adrenalin.     Arch.  f.  exper. 

Path.  u.  PharmakoL,  67,  247,  1912. 
Klinger,  Citation  in  Hess  and  Konigstein. 

Kocher,  Th.,  tJber  Kropfexstirpation  und  ihre  Folgen.     Arch.  f.  klin.  Chir.,  1883,  29. 
Kraepelin,  Lehrbuch  d.  Psychiatric.,  1896,  5,  Aufl. 
Kraus,  Fr.,  tJber  das  Kropfherz.     Wien.  klin.  Wchenschr.,  1899,  416  u.  Deutsche  med. 

Wchenschr.,  igo6,  1889. 
Krehl,  L.,  Uber  die  Storungen  chemischer  Korrelationen  im  Organismus.     Deutsches 

Arch.  f.  klin.  Med.,  88,  351-384,  1907,  and  Verhand.  deutsch.  Naturf.  u.  Arzte 

Stuttgart. 
Kren,  tJber  Sklerodermie  der  IMundschleimhaut.     Arch.  f.  Derm.  u.  Syph.,  95,  163. 
Laignel-Lavastine,  La  correlation  des  glandes  a  secretion  interne  et  leurs  syndromes 

pluriglandulaires.     Gaz.  d.  hop.,  1563,  1908. 
Langley,  J.  N.,  Observations  on  the  physiological  action  of  extracts  of  the  suprarenal 

bodies.     J.  Physiol.,  27,  237,  1901. 
Leredde  and  Thomas,  Sclerodermie  generalisee.     Arch.   d.   med.  exper.  et  d'anat.  path., 

1898,  665. 
V.  Leiibe,  Klin.  Bericht  von  der  Abteilung  des  Landeskrankenhauses  Erlangen,  1875,  28. 
Lichtwitz,  Uber  einen  Fall  von  Sklerodermie  und  Morbus  Addisonii.     Deutsches  Arch. 

f.  klin.  Med.,  94,  1908. 
Loewe,  S.,  Uber  Phosphorstoffwechsel  bei  Psychosen  und  Neurosen.     Ztschr.  f.  Neurol,  u. 

Psychiat.,  5,  445,  191 1. 
Lowi,  0.,  Eine  neue  Funktion  des  Pankreas,  etc.     Arch.  f.  exper.  Path.  u.  PharmakoL, 

59,  1908. 
Lorand,  Das  Altern.     Verlag  v.  Klinkhardt,  1910,  III,  Aufl. 
Marburg,  Die  Epiphyse.     Ergebn.  d.  Neurol.,  Springer,  1913. 
Marchand,  Des  Testicules  et  des  Ovaires  dans  la  Paralysie  generale.     Compt.  rend. 

Soc.  de  Biol.,  Paris,  Mai,  1903.     Reference  in  Rev.  neurol.,  Par.,  1904,  848. 
Marie,  Pierre,  Sur  deux  cas  d'acromegalie,  etc.     Rev.  d.  med.,  Par.,  6,  297,  1886. 
Markeloff,  G.  J.,  Uber  die  Myasthenic.     Arch.  f.  Psychiat.,  Berl.,  49. 
Martins,  Pathogenese  innerer  Krankheiten,  1899. 
Mering  and  Minkowski,  Diabetes  nach  Pankreasexstirpation.     Arch.   f.   exper.   Path. 

u.  PharmakoL,  26,  374,  1889. 
Mohitis,  Schilddriisentheorie.     Schmidt's  Jahrb.,  210,  237,  1886. 
Milller,  J.,  Lehrbuch  der  Physiologic.     I.  Koblenz,  1844. 
V.  Notthaft,  Neuere  Arbeiten  und  Ansichten  iiber  Sklerodermie.     Reference  Centralbl. 

f.  allg.  Path.  u.  path.  Anat.,  9,  870,  1898. 
Novak,  Die  Bedeutung  des  weiblichen  Genitales  fur  den  Gesamtorganismus.     Nothnagel, 

Supplbd.,  191 2. 
Opie,  E.  L.,  On  the  relation  of  chronic  interstitial  pancreatitis  to  the  islands  of  Langer- 

hans  and  to  diabetes  mellitus.     Exper.  Med.,  1901,  V,  397,  527. 
Ord,  W.  W.,  On  myxedema,  a  term  proposed,  etc.     Med. -Chir.  Tr.,   1879,  61.     Some 

cases  of  sporadic  cretinism.  Lancet,  1893. 
Osier,  see  Cassirer. 


GENERAL   PART  593 

Oswald,  Zur  Chemie  und  Physiologic  des  Kropfes.     Arch.  f.  path.  Anat.  [etc.]  Berl.,  169, 

1902. 
Paghini,  II  ricambio  organico  nella  demenza  precoce.     Riv.  sper.  di.  freniat.,  32  u.  33. 
Paliauf,  R.,  Discussion  on  Aschner's  demonstration.     K.  k.  Gesellsch.  d.  Arzte  in  Wien. 

Wien.  klin.  Wchenschr.  Dez.,  1909. 
Pfaundler,    tJber    Wesen    und    Behandlung    der    Diathesen    im    Kindesalter.     Referat, 

Kongr.  f.  inn.  Med.,  191 1. 
Pineles,  F.,  tJber  Thyreoaplasie,  etc.     Wien.  klin.  Wchenschr.,  1902,  Nr.  43.     Zur  Patho- 

genese  der  Tetanie.     Deutsches  Arch.  f.  klin.  Med.,  85,  1906. 
• — ■  Die  Beziehungen  der  Akromegalie,  zum  Myxodem  und  zu  anderen  Blutdriisener- 

krankungen.     Volkm.  Samml.  N.  F.,  1899,  242. 
Poetzl,  Eppinger,  and  Hess,  Uber  Funktionspriifungen  der  vegetativen  Nervensysteme 

bei  einigen  Gruppen  von  Psychosen.     Wien.  klin.  Wchenschr.,  1910,  Nr.  51. 
Pollitzer,  H.,  Uber  neurogene  Galektosurie.     Wien.  klin.  Wchenschr.,  25,  11 59,  191 2. 
Rapin,  E.,  Des  angio neuroses  familiales.     Rev.  med.  de  la  Suisse  Rom.,  1907. 
Rasch,  C,  Sklerodermie  mit  Affektion  der  Mundschleimhaut  und  Basedow  mit  Addison- 

Symptomen.     Dermat.  Ztschr.,  19,  244,  191 2. 
Raymond,  Soc.  neurol.  d.  Par.,  5  Febr.,  1903.     Rev.  neurol.,  1903,  245. 
Region,  Les   syndromes   polyglandulares   et   I'opotherapie   associee.     J.    d.   Practiciens, 

1908,  Nr.  30,  25  Juillet.,  465. 
Renon,  L.,  and  Pelille,  A.,  Insufi&sance  thyreo-ovarienne  et  hyperactivite  hypophysaire, 

etc.     Soc.  med.  des  hop.,  1908.,  19  Juin.,  973.     De  I'utilite  d'associer  les  medi- 
cations opotherapeutiques.     Soc.  de  therap.,  1907,  12  Juin,  289. 
Reverdin,  J.  and  A.,  Notes  sur  22  operations  du  goitre.     Rev.  med.  de  la  Suisse  Rom., 

1883. 
Rosenjeld,  tJber  den  Einfluss  psychischer  Vorgange  auf  den  Stoffwechsel.     AUg.  Zeitschr. 

f.  Psychiat.,  etc.,  Berl.,  63,  H.  3  u.  4  p.,  367. 
Roussy,  Les  glandes  a  secretion  interne.     Paris  med.,  191 1,  8  Juillet. 
Roux,  Sclerodermie  et  corps  pituitaire.     Rev.  neurol.,  1902,  721. 
Sattler,  Die  Basedowsche  Krankheit.     Leipzig,  1909  and  19 10,  Englemann. 
Sauerbeck,  Die  Langerhansschen  Inseln  im  normalen  und  kranken  Pankreas  des  Men- 

schen.     Arch.  f.  path.  Anat.  [etc.]  Berl.  177.     Supplementary  volume,  1904. 
Scholz,  W.,  Klinische  und  experimentelle  Untersuchungen  iiber  den  Kretinismus.     Berlin, 

1906. 
SchuUze,  W.,  Die  Bedeutung  der  Langerhansschen  Inseln  im  Pankreas.     Arch.  f.  mikr. 

Anat.,  56,  491,  1900. 
Seige,  cited  by  Kaufmann. 

Sicard  and  Roussy  {and  Berkowitsch),  cited  by  Gougerot. 
Singer,  Zur  Pathologie  der  Sklerodermie.     Ber.  klin.  Wchenschr.,  1895,  260. 
Ssoholew,  L.  W .,  Beitriige  zur  Pankreaspathologie.     Beitr.  z.  path.  Anat.  u.  z.  allg.  Path., 

47,  iQio- 
Stern,  R.,   tJber  korperliche  Kennzeichen    der    Disposition  zur  Tabes.     Fr.   Deuticke 

Leipzig  und  Wien,  191 2. 
Stiller,  Asthenische  Konstitutionskrankheit.     Stuttgart,  1907. 
V.  Strilmpell,  Ein  Beitrag  zur  Pathologie  und  pathologischen  i\natomie  der  Akromegalie. 

Deutsche  Ztschr.  f.  Nervenh.,  11,  87. 
Takamine,  The  isolation  of  the  active  principles  of  the  suprarenal  gland.     J.  Physiol.,  29, 

1901. 
Tandler  and  Grosz,  Die  Eunuchoide.     Arch.  f.  Entwicklungsmechanik  d.  Organ.,  Leipz., 

29,  1910. 
Tobias,  E.,  tJber  myasthenische  Paralyse,  etc.     Neurol.  Centralbl.,  31,  p.  551,  1912. 
38 


594  LITERATURE 

Vassale  and  Generali,  Sur  les  effets  de  I'exstirpation  des  glandes  parathyreoides.     Arch. 

ital.  de  biol.,  25,  459,  26,  61.     1896  u.  33,  1906. 
V.  Wagner,  Uber  endemischen  und  sporadischen  Kretinismus.      Wien.  klin.  Wchenschr., 

1900,  Nr.  19. 
Weichselbaum,  tjber  Veranderungen  des  Pankreas  bei  Diabetes.     Wien.  klin.  Wchenschr., 

1911,  Nr.  5. 
Wiesel,  Zur  Pathologie  des  chromaffinen  Systems.     Arch.  f.  path.  Anat.  [etc.],  Berl., 

176,  1904. 
Wunderlich,  Spec.  Pathol,  und  Therap.,  4,  1856. 
Ziilzer,  Untersuchungen  iiber  den  experimentellen  Diabetes.     24.  Kongr.  f.  inn.  Med., 

1907. 


CHAPTER  II 

THYROID  GLAND 

Abadie,  Traitement  chir.  du-goitre  exophthalmique.     Congr.  franf.  chir.,  Oct.,  1906. 
Abrikosojf,  Anatomischer  Befund  in  einem  Fall  von  Myxodem.     Arch.  f.  path.  Anat. 

[etc.],  Berl.,  177,  426,  1904. 
Andersson  and  Bergmann,  tjber  den  Einfluss  der  Schilddriisenfutterung,  etc.     Skandin. 

Arch.  f.  Physiol.,  8,  326,  1908. 
A  pelt,  Ein  Fall  von  Basedowscher  Krankheit  im  Anschluss  an  nicht  eitrige  Thyreoiditis 

acuta.     Miinchen.  med.  Wchenschr.,  41,  1908. 
Appert,  Myxoedeme  frusta,   croissance   tardif,   diabete.     N.   iconog.   de  la   Salpetriere, 

1904,  174. 

Argudinsky,  P.,  Ein  Beitrag  zur  Kenntnis  des  kongenitalen  Myxodems  und  der  Skelett- 
wachstumsverhaltnisse  bei  demselben.     Berl.  klin.  Wchenschr.,  1906,  1209. 

—  Abnormer  Tiefstand  des  Nabels  bei  angeborenem  Myxodem.     Berl.  klin.  Wchenschr., 

1905,  Nr.  35. 

Aschof,  tJber  einen  Fall  von  angeborenem  Schilddriisenmangel.  Deutsche  med.  Wchen- 
schr., 1899,  203,  Beil. 

Asher,  Kongr.  innere  Med.,  1906.     Discussion,  article  of  Fr.  Kraus. 

Asher  and  Flack,  Die  innere  Sekretion  der  Schilddriise.     Ztschr.  f.  Biol.,  60,  1910. 

Askanazy,  Pathologisch-anatomische  Beitrage  zur  Kenntnis  des  Morbus  Basedowi  usw. 
Deutsches  Arch.  f.  klin.  Med.,  65,  118,  1898. 

Ballet,  Gigantisme  et  goitre  exophthalmique.     Arch,  de  neurol.,  19,  1905. 

Ballet  and  Enriques,  Des  effets  de  I'hyperthyroidisation  experimentale.  Med.  mod.,  28, 
Dec,  1895. 

Balint  and  Molnar,  Durchfalle  bei  Basedowscher  Krankheit.  Deutsche  med.  Wchen- 
schr., 1910,  2211. 

Baruch,  Zur  experimentellen  Erzeugung  des  Morbus  Basedowi.  Centralbl.  f.  Chir., 
39,  316,  1912. 

V.  Basedow,  Exophthalmus  durch  Hypertrophic  des  Zellgewebes  in  der  Augenhohle. 
Wchenschr.  f.  d  ges.  Heilk,  13,  14,  1840. 

—  Die  Glotzaugen.     Ibidem,  49,  1848. 

Bayon,  tJber  die  Atiologie  des  Schilddriisenschwundes,  etc.     Neurol.  Centralbl.,  1906, 

792. 
Becker,  tJber  spontanen  Arterienpuls  in  der  Netzhaut  etc.  bei  Morbus  Basedowi.     Wien. 

med.  Wchenschr.,  1873,  Nr.  23. 
Beclere,  Un  nouveau  cas  de  myxoedeme  gueri  par  I'alimentation  thyreoide,  etc.     Bull. 

et  mem.  Soc.  med.  d.  Hop.  de  Par.,  12,  Sept.,  1894,  931. 
Bence,  J.,  and  Engel,  K.,  Uber  Veranderung  des  Blutbildes  beim  Myxedema.     Wien. 

klin.  Wchenschr.,  1908,  Nr.  25. 
Betard,  Corps  thyreoides.     Paris,  Baillere  freres,  1908. 
Bergeat,   Uber  300  Kropfexstirpationen  an  der  Brunsschew  Klinik,  1884-1894.     Beitr. 

z.  klin.  Chir.,  15,  1890. 
V.  Bergmann,  Der  Stoff-  und  Energieumsatz  beim  infantilen  Myxodem.     Ztschr.  f.  exper. 

Path.  u.  Pharmakol.,  5,  page  646,  1909. 
Bernheim-Karrer ,  tJber  zwei  atypische  Myxodemfalle.     Ztschr.  f.  Kinderheilk,  64. 

595 


598  LITERATURE 

Erb.  ir.,  Uber  :Myx6dem.     Berl.  klin.  Wchenschr.,  1887. 

Erdlieim,  Uber  Schilddruscnaplasie  bei  Kretinismus,  etc.     Beitr.  z.  path.  Anat.  u.  z.  allg. 

Path.,  35,  366,  1Q04. 
d'Espiiie,  cited  by  Breiier. 
Esser.    Blut    und    Knochenmark    nach    Ausfall    der    Schilddriisenfunktion.     Deutsches 

Arch.  f.  klin.  Med..  89,  p.  576,  1907. 
Ewald,  Uber  einen  durch  die  Schilddriisentherapie  geheihen  Fall  von  ^lyxodem,  etc. 

Berl.  klin.  Wchenschr.,  1895.  Xr.  2. 

—  Die  Erkrankungen  der  Schilddriise,  jNIyxodem  und  Kretinismus.     II.  Aufl.  Leipzig 

u.  Wien.,  1909,  A.  Holder. 

—  Adenokarzinom  der  Schilddriise.     Wien.  klin.  Wchenschr.,  1S96. 

Fakkenberg,   Zur  Exstirpation  der   Schilddruse.     X.   Kongr.  inn.  ]Med.,  p.  502,    1891. 
Falta,  W.,  Uber  die  Korrelationen  der  Driisen  mit  inner  Sekretion.     Ergebn.  d.  wissenschii., 
jMed.,  1910. 

—  Uber  Glykosurie  und  Fettstiihle  bei  Morbus  Basedowi.  etc.     Ztschr.  f.  klin.,  jSIed., 

71,  1910. 

—  Weitere  Mitteilungen  iiber  die  Wechsehvirkung  der  Driisen  mit  innerer  Sekretion. 

Wien.  klin.  Wchenschr.,  1909,  Xr.  30. 
Falta,  TU.,  and  G.  B.  Fleming,  Uber   die  Wirkung   des   Adrenalins  und   Pituitrins,  etc. 

Miinchen.  med.  Wchenschr.,  191 1,  Xr.  50. 
Falta  and  Kaliii,  Studien  iiber  die  Tetanic,  etc.     Ztschr.  f.  klin.  INIed.,  74,  191 1. 
Falta,  Newburgli,  and  NobcL  Wechselwirkung  der  Driisen  mil  innerer  Sekretion.     IV. 

Uberfunktion  und  Konstitution.     Ztschr.  f.  klin.  ]Med.,  72,  191 1. 
Falta  and  Rudinger,  Studien  iiber  Tetanic.     Kongr.  f.  innerc  Med.,  1909. 
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Wien.  klin.  Wchenschr.,  1900,  6. 
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Centralbl.  f.  Physiol.,  1910. 

—  Zur  Frage  der  regionar  vcrschiedenen  Empiindlichkcit  gegen  Jod.     Miinchen.  med., 

Wchenschr.,  191 1,  4. 
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Thyreoidin  auf  den  Stickstoffwechscl,  etc.     Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir., 

24,  123,  1911. 
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1896. 
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Morbus  Basedowi.     Arch.  f.  exper.  Path.  u.  Pharmakol.,  60,  1909. 
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Arch.  f.  d.  ges.  Physiol.,  124,  1908. 


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6oO  LITERATURE 

Hectoen,  Ein  Fall  von  Scleroderma  diffusum.     Centralbl.  f.  allg.  Path.  u.  path.  Anat., 

1897,  Nr.  17. 
Heintzheimer,    Entwicklung    und    gegenwartiger    Stand    der    Schilddriisenbehandlung. 

Miinchen,  1895. 
Hertoghe,  Influence  des  produits  thyreoidiens,  etc.     Bull.  Acad.  roy.  de  med.  de  Belg. 

X,  1896,  p.  381. 
Hertoghe-Spiegelherg,  Die  RoUe  der  Schilddriise  bei  Stillstand  und  Hemmung  des  Wach- 

stums,  etc.     Miinchen,  1900,  Lehnaann. 
Herz,  A.,  Verhandl.  d.  Gesellsch.  f.  innere  Med.,  4,  Juni,  1908. 
Himmelheber,  Akute  Thyreoiditis  als  Komplikation  nach  einer  Operation.     Centralbl. 

f.  Gynak.,  35,  1909. 
Hirsch,   R.,   Glykosurie  nach  Schilddriisenexstirpation  bei  Hunden.     Ztschr.   f.   exper. 

Pathol,  u.  Therap.,  3,  1906. 
Hirschl,  J.  A.,  Osteomalacie  bei  Morbus  Basedowi  und  Myxodem.     Jahrb.  f.  Psychiat. 

u.  Neurol.,  20,  406,  iqoi,  und  Wien.  klin.  Wchenschr.,  1901,  333. 

—  Uber  Geistesstorungen  bei  Morbus  Basedowi.     Jahrb.  f.  Psychiat.  u.  Neurol.,  1894, 

p.  52. 
HirscJdaJf,  W.,  Zur  Pathologic  und  Klinik  des  ^Morbus  Basedowi.     Ztschr.  f.  klin.  ^Med., 

36,  200,  1899. 
Hofbauer,  Typische  Atemstorungen  bei  Morbus  Basedowi.     Mitt.  a.  d.   Grenzgeb.  d. 

Med.  u.  Chir.,  Nr.  11,  531. 
Hofmeister,  Experimentelle  Untersuchungen  iiber  die  Folgen  des  Schilddriisenverlustes. 

Beitr.  z.  klin.  Chir.,  11,  1894  und  Deutsche  med.  Wchenschr.,  1896,  Nr.  22. 
Honnicke,  Discussion  on  Kocher's  lecture.     Kongr.  f.  inn.  Med.,  1906,  108. 
Holmgren,  J.,  Uber  das  Langenwachstum  bei  Hyperthyreose.     Med.  Klin.,  1910.     Uber 

den    Einfluss    der    Basedowschen    Krankheit,    etc.,    auf    das    Langenwachstum. 

Leipzig,  1909. 
Holzknecht,  Gesellschaft  der  Arzte.     Wien.  klin.  Wchenschr.,  1909,  Nr.  47. 
Horsley,   Die   Funktion  der  Schilddriise,   eine  historisch-kritische   Studie.     Fstschr.   f. 

Virchow,  i,  Berlin,  1891. 
Hotz,  Die  Ursache  des  Thymustodes.     Beitr.  z.  klin.  Chir.,  55,  p.  509,  1907. 
Huchard,  Nature  et  traitement  du  goitre  exophthalmique.    J.  des  praticiens,  1900,  157. 
Hunt,  Reid,  Influence  of  thyroid  feeding  and  of  various  foods  and  of  small  amount  of  food 

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—  The  relation  of  iodin  to  the  thyroid  gland.     J.  Am.  ]\L  Ass.,  1907. 

—  The  probable  demonstration  of  thyroid  secretion  in  the  blood  in  exophthalmic  goiter. 

Ibidem,  1907. 
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Treasury  Department. 
Jaboulay,  Resection  bilaterale  du  sympathique  cervical  dans  le  goitre  exophtalmique. 

Bull.  Acad,  de  med.,  38,  1897. 
V.  Jaksch  and  H.  Rotky,  Uber  eigenartige  Knochenveranderungen  im  Verlauf  des  ]Morbus 

Basedowi.     Fortschr.  a.  d.  Geb.  d.  Rontgenstrahlen,  13,  1908. 
Jaquet  and  Svenson,  Stoffwechsel  fettsiichtiger  Individuen.     Ztschr.  f.  klin.  jNIed.,  41,  375, 

1900. 
Jeanselme,  Thyreoidite  et  Strumite  infectieuse.     Gaz.  d.  Hop.,  1895. 
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basedow.     Arch,  de  med,  exper.  et  d'anat.  path.,  5,  807,  1893. 
Jones,  Exophthalmic  goiter  and  rheumatoid  arthritis.     Lancet,  16,  Jan.,  1909. 
Jonescu,  cited  in  Jahresb.  f.  Fortschr.  a.  d.  Geb.  d.  Chir.,  1901,  p.  454. 


THYROID    GLAND  6oi 

Kahler,  0.,  Uber  den  Leitungswiderstand  der  Haut  bei  Morbus  Basedow!.     Prag.  Ztschr. 

f.  Heilk.,  9,  i8S8. 
Kappis,  M.,  tjber  Hirnnervenlahmungen  bei  der  Basedowschen  Krankheit.     Mitt.  a.  d. 

Grenzgeb.  d.  Med.  u.  Chir.,  22,  191 2,  Heft,  4. 
Kappis,  Uber  Lymphocytose  des  Blutes  bei  Basedow  und  Struma.     ]Mitt.  a.  d.  Grenzgeb. 

d.  Med.  u.  Chir.,  21,  1910,  p.  729. 
Kashiwaniura,  Die  Schilddriise  bei  Infektionskrankheiten.     Arch.  f.  path.  Anat.  [etc.], 

Berl.,  166,  373. 
Kassowitz,  Infantiles  Mxyodem,  ]\Iongolismus  und  jNIikromeHe.     Wien.  med.  Wchenschr., 

Nr.  22  u.  Fortsetzung,  1902. 
Kaufmann,  E.,  Untersuchungen  iiber  die  sog.  fotale  Rachitis.     Berlin,  1892. 
Kirk,  Notes  on  cases  of  myxodema.     Lancet,  2,  743,  1893. 
Kishi,  Beitrage  zur  Physiologic  der  Schilddriise.     Arch.  f.  Path.  Anat.  [etc.],  Berl.,  176, 

p.  260. 
Kleinwdchter,  Wie  ist  der  Genitalbefund  bei  Morbus  Basedowii?     Ztschr.  f.  Geburtsh. 

u.  Gynaek.,  16,  144,  1889. 

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10,  181. 
Klemm,  Die  operative  Therapie  des  jNIorbus  Basedowi.     Arch.  f.  klin.  Chir.,  86. 
Knopfelmacher,    Alimentare    Glykosurie    und    Myxoedem.     Wien.  klin.  Wchenschrift., 

1904,  224. 
— •  Wien.  klin.  Wchenschr.,  1902,  Nr.  28,  p.  712. 

—  Zwei  Falle  von  Myxodem,  etc.     Wien.  klin.  Wchenschr.,  1905,  296. 
Kocher,  A.,  Uber  Jodbasedow.     Arch.  f.  klin.  Chir.,  92,  Heft,  5. 

—  Uber  Morbus  Basedowi.     Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  9,  1902. 

—  Uber  die  Ausschiedung  des  Jods  im  menschlichen  Organismus,  etc.     Ibidem,  14,  1905. 

—  Blutuntersuchungen  bei  Morbus  Basedowi,  etc.     Arch.  f.  klin.  Chir.,  87,  1908. 

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677. 
Kocher,  Th.,  Surgical  Congress.     Berhn,  191 2. 

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—  Blutuntersuchungen  bei  Morbus  Basedowi.     Arch.  f.  klin.  Chir.,  87,  1908. 
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— •  Uber  Kropf  und  seine  Behandlung.     Deutsche  med.  Wchenschr.,  38,  1265,  191 2. 
Kocher-Langhans ,  Deutsche  Ztschr.  f.  Chir.,  34,  1892,  and  Arch.  f.  Path.  Anat.  [etc.  ],  Berl., 

128,  318. 
Kohler,  R.,  Myxodem  auf  Syphilis  beruhend.     Berl.  klin.  Wchenschr.,  1892,  743,  and  1894, 

41. 
V.  Korczynski,  Einige  Bemerkungen  iiber  das  Myxodem.     Wien.  med.  Presse,  1898,  Nr. 

36-37- 
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—  tJber  das  Kropfherz.     Wien.  khn.  Wchenschr.,  1899,  416,  und  Deutsche  med.  Wchen- 

schr., 1906,  1889. 


602  LITERATURE 

Kraus,  Fr.,  and  Friedenthal,  Uber  die  Wirkung  der  Schilddriisenstoffe.     Berl.  klin.  Wchen- 

schr.,  1908,  1709. 
Kraus  and  Liidwig,  Klinische  Beitrage  zur  alimentaren  Glykosurie.     Wien.  klin.  Wchen- 

schr.,  1891,  898. 
Krehl,  Miinchen.  med.  Wchenschr..   1910.  Xr.  47. 
Kroug,  E.,  cited  by  Sattler.     Lit.  Xr.  2700. 
Lampe,  Liesegang,  and  Klose,  Die  Basedowische  Krankheit,  etc.     Beitr.  z.  klin.  Chir.,  77, 

1912. 
Landstrom.  J..  Uber  Morbus  Basedowi.  etc.     Stockholm.  1907. 
Lange,  Die  Beziehungen  der  Schilddriise  zur  Schwangerschaft.     Ztschr.  f.  Geburtsh.  u. 

Gynaek.,  14,  1899. 
Langhans,  Uber  \'eranderungen  in  den  peripheren  Xerven  bei  Cachexia  thyreopriva  des 

^lenschen  und  Aft'en,  etc.     Arch.  f.  Path.  Anat.  [etc.],  Berl.,  128,  318,  1892. 
Lanz,  Uber  Schilddriisenfieber  und  Schilddriisenintoxikation.     ]\Iitt.  a.  d.  Grenzgebiet 

d.  Med.  u.  Chir.,  8,  1901. 
—  Ein  Vorschlag  zur  diatetischen  Behandlung   Basedowkranker.     Cor.-Bl.  f.  schweiz. 

Aerzte,   1899,  u.  Weitere  ^litteilungen  iiber  serotherapeutische  Behandlung  des 

Morbus  Basedowii.     Miinchen.  med.  Wchenschr.,  1903. 
Lawson,  Tail,  Reference  in  Schmidt's  Jahrb..  168,  34,  1875. 
Lebert,  cited  by  Breuer. 

Leichtensteru ,  Uber  Myxodem  und  Entfettungskuren  mit  Schilddriisenfutterung.     Deut- 
sche med.  Wchenschr.,  1894,  Xr.  50. 
Leischner  und  Marburg,  Zur  Frage  der  chirugischen  Behandlung  des  Morbus  Basedowi. 

Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir..  21,  761,  1910. 
Lepi)ie,  Lyon  Med.,  1903,  loi. 
Leredde  and  Thomas,  Sclerodermie  generalisee.     Arch,  dc  med.  exper.  et  d'anat.  path., 

1898,  665. 
V.  Leube,  Klinischer  Bericht  von  der  Abteilung  des  Landeskrankenhauses  Erlangen,  1875, 

28. 
Lcwin,  Zur  Kasuistik  des  Morbus  Basedowi.     Inaug.-Diss.  Berlin,  1888. 
van  Lier,  Blutuntersuchung  bei  Morbus  Basedowi.     Beitr.  z.  klin.  Chir.,  69. 
Lorand,  Uber  das  Altcrn,  Verl.  v.  KHnkhardt.,  1910,  3,  Aufl. 
Loeb,  7.,  in  Oppenheimers  Handbuch  der  Biochemic,  2,  i,  1910. 
Loeu\  /.,  Uber  das  Auftreten  von  Odemen  beim  Morbus  Basedowi.     Wien.  med.  Presse, 

38,  721,  1897. 
Locii'i,  O.,  Eine  neue  Funktion  des  Pankreas,  etc.     Arch.  f.  exper.  Path.  u.  Pharmakol., 

59,  1908. 
Loivy,  J.,  Uber  Basedowsymptome  bei  Schilddriisenneoplasmen.     Wien.  klin.  Wchenschr., 

1909,  1671. 
Lubarsch,   Schilddriisenveranderung   bei  Basedowscher   Krankheit.     Centralbl.   f.   allg. 

Path.  u.  path.  Anat.,  6,  716,  1895. 
Mabille,  De  I'efficacite  de  I'arsene  contre  I'accident  de  la  medication  thyreoide.     Paris, 

1899. 
MacCallum  and  Fabyan,  On  the  anatomy  of  a  myxedematous  idiot.     Johns  Hopkins 

Hosp.  Bull.,  18,  198,  Sept.,  1907. 
Maccone,  L.,  Beitrag  zum  Studium  der  histologischen  Veranderungen  bcim  kindlichen 

Myxodem.     Pediatria,  6. 
Mac  fie  Campbell,  cited  by  Bouchan. 

Maclll-wine,  Myxedema  in  mother  and  child.     Brit.  ^L  J.,  May,  24,  1902,  1261. 
Mackenzie,  H.,  A  lecture  on  Graves'  disease.     Brit.  ^L  J.,  1905,  1077. 
Macpherson,  Thyreoid  grafting  in  myxedema.     Edinb.  ^L  J.,  May,  1892. 


THYROID    GLAND  603 

Magnus-Levy,  A.,  Untersuchungen  zur  Schilddriisenfrage.  Zschr.  f.  klin.  I\Ied..  33  u.  60, 
1897. 

—  IJber  Myxodem.     Ztschr.  f.  klin.  Med.,  52,  1904. 

Marafion,  G.,  La  Hiperchlorhidria  en  el  Hiperthiroidismo.     Rev.  Ibero.  Am.  de  cien.  med. 

Junio,  191 2. 
Maresch,   Kongenitaler  Defekt  der  Schilddriise  bei  einem   11   jahrigen  ]\Iadchen,   etc. 

Ztschr.  f.  Heilk.,  19,  1S98. 
Mai'fand,  Thyreoidite  rheumatismale  avec  myxoedeme  et  vitiligo.     Bull,  de  med.,  Paris, 

33,  1900- 
Marie,  Pierre,  Contribution  a  I'etude  et  au  diagnostic  des  formes  frustes  de  la  maladie  de 

Basedow.     These  de  Paris,  1883. 
Marinesco  and  Minea,  Nouvelles  recherches  sur  I'influence  qu'exerce  I'ablation  du  corps 

thyroide,  etc.     Compt.  rend.  Soc.  d.  biol.,  19 10,  Nr.  4. 
Matthes,  Zum  Stoffwechsel  bei  ^Morbus  Basedowi.     Kongr.  f.  innere  Med.,  1897,  232. 
Maurer,  Die  Entwicklung  des  Darmsystems.     Hertwigs  Handb.  d.  vgl.  Entwicklungs- 

gesch.,  2,  I,  1906. 
Mayerle,  Beitr.  zur  Kenntnis  des  Stoffwechsels  bei  kiinstlicher  Hyperthyreoiditis.     Ztschr. 

f.  klin.  Med.,  71. 
Mayo,  A  consideration  on  the  mortality  in  one  thousand  operations  for  goiter,  etc.     Surg. 

Gynec.  and  Obst.,  March,  1909,  8. 
McCarissoH,  Lancet  2,  p.  1570,  1906. 

Meltzer,  Uber  Myxodem.     New  Yorker  med.  IVIonatschr.,  April,  1894. 
Mendel,  Zur  pathologischen  Anatomic  des  ]\Iorbus  Basedowi.     Deutsche  med.  Wchen- 

schr.,  1892,  5,  und  ein  Fall  von  Myxodem  ibidem,  1893,  25. 
Meunacher,  Blutbefund  beim  Myxodem.     Monatschr.  f.  Kinderheilk.,  6,  666,  1907. 
V.  Mikulicz,  Die  Thymusfiitterung  bei  Kropf,  etc.     Berl.  klin.  Wchenschr.,  1895,  16. 
V.  Mikulicz  and  Reinhach,  Uber  Thyreoidismus.     Mitt.  a.  d.  Grenzgeb.  d.  IVIed.  u.  Chir.,  8, 

1901. 
Minnich,  W .,  Das  Kropfherz,  etc.     Leipzig  u.  Wien,  1904,  Fr.  Deuticke. 
Mobiles,  P.  J.,  Schmidt's  Jahrb.,  210,  237,  1886. 

—  Die  Basedowsche  Krankheit.     Wien,  1906,  Holder. 

—  Miinchen.  med.  Wchenschr.,  1903,  Xr.  4. 

Moszkowicz,  Protokoll  der  k.  k.  Gesellsch.  der  Artze  in  Wien,  1908.  Wien.  klin.  Wchen- 
schr., 304,  1908. 

Mailer,  Charlotte,  Uber  morphologische  Blutveranderungen  bei  Struma.  Med.  Klin., 
1910,  Nr.  34. 

Mailer,  Fr.,  Beitrage  zur  Kenntnis  der  Basedowschen  Krankheit.  Deutsches  Arch.  f. 
klin.  Med.,  51,  335,  1893. 

—  Discussion  on  Referat  of  Fr.  Kraus.     Kongr.  f.  innere  Med.,  1906. 

V.  Mailer,  A.  andP.  Saxl,  tjber  Kalziumgelatineinjektionen.     Therap.  ^Nlonatsh.,  26,  1912. 
Munk,  H.,  Zur  Lehre  von  der  Schilddriise.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  115,  1897, 

u.  154,  1898. 
Muratov,  Zur  Pathologic  des  Myxodems.     Xeurol.  CentralbL,  189S,  20. 
Murray,  G.  R.     The  diagnosis  of  early  thyreoidal  fibrosis.     Transact,  of  the  Roy.  med.  a. 

chir.  Soc,  1902,  141.     (Ref.  Brit.  AI.  J.,  1898,  942.) 
Mygind,  Thyreoiditis  acuta  simplex.     J.  Laryngol.,  1895,  iSi- 
V.  Noorden,  Die  Zuckerkrankheit.     \'.  Auti.  Hirschwald,  19 10. 

—  Discussion  on  Morbus  Basedowi.     K.  k.  Gesellsch.  d.  Arzte  Wiens,  1909,  1769. 

—  Sammlung  klinischer  Abhandlungen,  Berlin,  1909,  48,  Hirschwald. 

—  Die  Fettsucht.     II.  Aufl.,  Holder,  1910. 


604  LITERATURE 

V.  Noorden,  Jr.,  Zur  Kenutnis  der  vagotonischen  unci  sympathikotonischen  Falle  von 

Morbus  Basedowii.     Inaug.-Diss.,  Kiel,  igii. 
V.   Notthaft,   Neuere  Arbeiten  und  Ansichten  iiber   Sklerodermie.     Centralbl.   f.   allg. 

Path.  u.  path.  Anat.,  9,  870,  1898. 
■ —  Ein  Fall  von  artifiziellem  akut  thyreogenem  ^Morbus  Basedow!,  etc.     Centralbl.  f. 

innere.  Med.,  1898,  Nr.  15. 
Notki,  Beitrag  zur  Schilddriisenpathologie.     Wien.   med.  Wchenschr.,   1896.     Arch.  f. 

path.  Anat.  [etc.],  Berl.,  144,  Suppl. 
Novak,  J.,  Die  Erkrankungen  des  weiblichen   Genitales  in  ihrer  Bedeutung  fiir  den 

Gesamtorganismus     und     die     Wechselbeziehungen     seiner    innersekretorischen 

Elemente  zu  den  anderen  Blutdriisen.  Suppl.  to  Xothnagel's  Pathol,  u.  Therap. 

A.  Holder,  Wien  u.  Leipzig,  191 2. 
Oliver  and  Schdjer,  The  physiological  effects  of  extracts  of  the  suprarenal  capsules.     J. 

Physiol.,  18,  231,  1895  und  On  the  physiological  action  of  extracts  of  pituitary 

body,  etc.,  ibidem,  18,  277,  1895. 
Oppenheim,  fl^.,  Lehrb.  d.  Nervenkrankh.  1908,  1550  u.  1911,  183. 
Ord,  Med.  Chir.  Tr.,  61,  1878. 

Ortner,  Vorlesungen  iiber  spezialle  Therapie  innere  Krankheiten,  etc. 
Osier,  W.,  An  acute  myxoedematous  condition  with  tachycardia,  glycosuria,  melaena, 

mania  and  death.     J.  Xerv.  Ment.  Dis.,  26,  68,  1899. 

—  Cited  by  Cassirer. 

Oswald,  Der  Morbus  Basedow!  im  Lichte  neuercr  klinischer  und  experimenteller  For- 

schung.     Wien.  klin.  Wchenschr.,  1900. 
Oswald,  Die  Chemie  und  Physiologic  des  Kropfes.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  169, 

1902. 

—  Zur  Klarung  der  Jodothyrinfrage.     Arch.  f.  d.  ges.  Physiol.,  129,  1909. 

Pdssler,  Erfahrungen  iiber  die  Basedowsche  Krankheit.  Deutsche  Zschr.  f.  Nervenh., 
6,  1895. 

Pari,  G.  A.,  tjber  den  Einfluss  der  Schilddriise  auf  den  zeitlichen  Ablauf  der  Zersetzungen. 
Biochem.  Ztschr.,  13,  1908. 

Parhon  and  Marhe,  Contribution  a  I'etude  des  troubles  mentaux  de  la  maladic  de  Base- 
dow.    Encephale,  5,  1906. 

Parhon  and  Papinian,  Ein  Fall  von  chronischem  dysthyreoid.  Rheumatismus.  Buka- 
rester  med.  Gesellsch.,  1904. 

Paterson,  Notes  on  the  etiology  of  Graves'  disease.     Lancet,  June,  1894,  1370. 

Payr,  E.,  Transplantation  der  Schilddriise  in  die  jSIilz.     Arch.  f.  klin.  Chir.,  80,  1906,  730. 

Peucker,  tJber  einen  Fall  von  kongenitalem  Defekt  der  Schilddriise,  etc.  Ztschr.  f.  Heilk, 
20,  341,  1899. 

Pick  and  Pineles,  Untersuchungen  iiber  die  physiologisch  wirksame  Substanz  der  Schild- 
driise.    Ztschr.  f.  exper.  Path.  u.  Therap.,  1909,  Nr.  7. 

Pilcz,  Zur  Frage  des  myxodematosen  Irreseins.     Jahrb.  f.  Psychiat.,  1901,  77. 

Pineles,  tJber  die  Empiindlichkeit  des  Kropfes  gegen  Jod.  Wien.  klin.  Wchenschr.,  1910, 
Nr.  10. 

—  tJber  Thyreoaplasie,  etc.     Wien.  klin.  Wchenschr.,  1902  u.  Wien.  klin.  Wchenschr., 

1912,  Nr.  43. 

—  Volkmann's  Vortr.,  1899,  Nr.  242. 

Ponfick,  see  multiple  ductless  glandular  sclerosis.  Chapter  XI. 

Porges  and  Pribram,  tJber  den  Einfluss  verschiedenartiger  Diatformen  auf  den  Grundum- 

satz  bei  Morbus  Basedowii.     Wien.  klin.  Wchenschr.,  1584,  1908. 
Pribram,  Basedowsche  Krankheit.     Prag.  med.  Wchenschr.,  438,  1882. 


THYROID    GLAND  605 

de  Quervain,  Die  akute  nicht  eitrige  Thyreoiditis.     INIitt.  a.  d.  Grenzegeb.  d.  Aled.  u.  Chir. 

SuppL,  2,  1904. 
Quine,  Medical  treatment  of  exophtlialmic  goiter  J.  Am.  M.  Ass.,  1907,  350. 
Quincke,  Uber  Athyreosis  im  Kindesalter.     Deutsche  med.  Wchenschr.,  1900,  787. 
Reinbach,   tjber  das  Verhalten  der  Temperatur  nach  Kropfoperationen.     Mitt.   a.   d. 

Grenzgeb.  d.  Med.  u.  Chir.,  4,  606,  1899. 
Reinhold,  Zur  Pathologic  der  Basedowschen  Krankheit.     Munchen.  med.  Wchenschr., 

1894,  Nr.  23. 
Reinlinger,  Cited  by  de  Quervain. 
Reverdin,  J.  and  A..  Notes  sur  22  operation  de  goitre.     Rev.  med.  de  la  Suisse  Romain, 

1883. 
Revilliod,  L.,  Le  thyreoidisme,  etc.     Rev.  med.  de  la.  Suisse  Romain,  15,  413,  1895. 
Rillier,  F.,  Memoire  sur  I'iotisme  constitutionelle.     Paris,  i860. 
Roasenda,  G.,  Contributo  alio  studio  ed  all  interpretazione  del  Alorbo  di  Flagani-Basedow. 

Rev.  neuropat.,  3,  1909. 
Rocaz  and  Cruchet,  Myxoedeme  congenitale.     Arch,  de  med.  d.  enf.,  6,  97,  1905. 
Roger  and  Gamier,  La  glande  thyreoidea  dans  les  malad.  infect.     Presse  med.,  1899,  181. 
Rogowitsch,    Die    Veranderungen    der   Hypophyse    nach    Entfernung    der    Schilddriise. 

Beitr.  z.  path.  Anat.  u.  z.  aUg.  Path.,  4,  453,  1898. 
Roos,  tJber  die  Einwirkung  der  Schilddruse  auf  den  StoftVechsel.     Ztschr.  f.  physiol. 

Chem.,  21,  1895. 
Rossin  and  Jellinek,  Uber  Farbekraft  und  Eisengehalt  des  menschhchen  Blutes.     Ztschr. 

f.  klin.  Med.,  39,  109,  1900. 
Rossle,  Tiber  Hypertrophic  und  Organkorrelationen.     jNIiinchen.  med.  Wchenschr.,  1908, 

Nr.  8. 
Roth,  Das  Blutbild  beim  Morbus  Basedow!.     Deutsche  med.  Wchenschr.,  Februar,  1910. 
Rothschild  and  Lewi,  Etude  sur  la  physiopathologie  du  corps  thyreoide,  etc.     Paris,  1908. 
Roiix,  Sclerodermic  et  corps  pituitaire.     Rev.  neurol.,  1902,  721. 

Rudinger,  Uber  Eiweissumsatz  bei  Morbus  Basedowi.     Wien.  klin.  Wchenschr.,  1908. 
Sainton  and  Rathery,  see  multiple  ductless  glandular  sclerosis.  Chapter  XL 
Salomon,  H.,  Gaswechseluntersuchungen  bei  Morbus  Basedowi.     Berl.  klin.  Wchenschr., 

1904,  Nr.  24. 
Salomon  and  Amalgia,  Uber  Durchfalle  bei  ]Morbus  Basedowi.     Wien.  klin.  Wchenschr., 

1908,  870. 
Saltykow,  Sarkom  und  Karzinom  in  der  Schilddruse.     Centralbl.  f.  allg.  Path.  u.  Anat., 

16,  547,  1905- 
Sarbach,  Das  Verhalten  der  Schilddruse  bei  Infektionen  und  Intoxikationen.     Mitt.  a.  d. 

Grenzgeb.  d.  Med.  u.  Chir.,  15,  1905. 
Sattler,  Die  Basedowsche  Krankheit.     Leipzig,  1909  u.  1910,  Engelmann. 
Schilder,  P.,  Uber  Missbildungen  der  Schilddruse.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  203, 

246,  1911. 
Schkarine,  Reference  in  Rev.  neurol.,  20,  1908  (Russian). 
Schlesinger,  H.,  Meine  Erfahrungen  iiber  den  akuten  Morbus  Basedowii.     Therapie  der 

Gegenwart,  488,  191 2. 
Schmidt,  Adolf,  Discussion  on  the  lecture  on  "Fettstiihle"  by  H.  Salomon.     20  Kongr.  f. 

innere  Med.,  1902. 
Scholz,  W.,  See  Cretinism,  Chapter  III. 
Schotten,  tJber  Myxodem  und  seine  Behandlung  mit  innerlicher  Darreichung  von  Schild- 

driisensubstanz.     Munchen.  med.  Wochenschr.,  1893,  Nr.  51,  52. 
V.  Schrotter,  L.,  Zum  Symptomenkomplex  des  Morbus  Basedowi.     Ztschr.  f.  klin.  Med., 

48,  I,  1903. 


6o6  LITERATURE 

Schultze,  K.,  Experimentelle  Untersuchungen  iiber  das  Fieber  nach  Kropfoperationen. 
Mitt.  a.  d.  Grenzgeb.  d.  ]\Ied.  u.  Chir.,  17,  655,  1907. 

—  Zur  Chirurgie  des  Morbus  Basedowi.      ■\Iitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  16, 

161,  1906. 
Schwarz,  G.,  Rontgentherapie  der  Basedowschen  Krankheit.     Wien.  klin.  Wchenschr., 

1908,  1332. 
Seltowitsch,  Ein  Fall  von  Struma  accessoria  der  Zungenbasis.     Entstehung  eines  Myxo- 

dems  nach  Entfernung  desselben.     Centralbl.  f.  Chir.,  24. 
Schif,  Bericht  iiber  eine  Versuchsreihe  betr.  die  Exstirpation  der  Schilddriise.     Arch.  f. 

exper.  Path.  u.  Pharmakol.,  18,  1884. 
Short,  Iodoform  and  thyroidism.     Bristol  M.  Chir.  J.,  June,  1910. 
Sicheumann,  Uber  die  Funktion  und  die  mikroskopische  Anatomic  des  Gehororgans  bei 

totaler  Aplasie  der  Schilddriise.     Arch.  f.  Ohrenh.,  70,  1907. 

—  See  Diederle. 

Siegert,  F.,  Myxodem  im  Kindersalter.     Ergebn.  d.  innere  Med.  u.  Kinderh.,  6,  1910,  601. 
Singer,  Zur  Pathologic  der  Sklerodermie.     Berl.  klin.  Wchenschr.,  1895,  266. 
Sollier,  P..  Maladie  de  Basedow  avec  myxoedeme.     Rev.  de  med.,  11,  1000,  1891. 
Spiethof,  B.,  Blutdruckmessung  bei  INIorbus  Basedowi.     Centralbl.  f.  innere.  ]\Ied.,  34, 

1892. 
Spoherini,  L.  M.,  De  I'influence  nocive  sur  le  nourissant,  etc.     Rev.  de  I'hygiene  et  de 

med.  inf.  letc],  8,  i,  1909. 
Starr,  Alien.  A  contribution  to  the  subject  of  myxedema.     N.  York  Med.  Rec,  June, 

1893. 
Stern,   R.,   Diflferentialdiagnose   und    \'erlauf   des   Morbus   Basedowii,    etc.     Jahrb.    f. 

Psychiat.  u.  Neurol.,  29,  1909. 
Steyrer,  A.,  Ztschr.  f.  exper.  Path.  u.  Therap.,  4,  1907. 
Stick  and  Makkas,  Zur  Transplantation  der  Schilddriise  mittelst  Gefiissnaht.     Beitr.  z. 

klin.  Chir.,  60. 
Strauss,  H.,  ZurLehre  von  der  neurogenen  und  thyreogenen  Glykosurie.     Deutsche  med. 

Wchenschr.,  1897,  Xr.  18  u.  20. 
Stubcnrauch,    Knochenveranderungen    bcim    Myxodem.     Berl.    klin.    Wchenschr.,    76, 

860,  1911. 
Stiive,  Festschr.  d.  stiidt.  Krankenhauses  Frankfurt  a.  ]M.,  1896. 
Syllaba,  L.,  Uber  die  Prognose  bei  der  Basedowschen  Krankheit.     Wien.  med.  Blr.,  1909, 

322. 
Thick  and  Nchring,  Untersuchungen  des  respiratorischen  Gaswechsels  unter  dem  Einfluss 

von  Thyroideapraparaten,  etc.     Ztschr.  f.  klin.  Med.,  30,  41,  1895. 
Thomas,  Enc'in,  Zur  Einteilung  der  ^Nlyxodemformcn.     Deutsche  med.  Wchenschr.,  191 2, 

461. 
Thorbccke,  Dissertation.     Heidelberg.  1905. 
Trousseau,  Du  goitre  cxophtalm.     Union  med..  Par.,  i860.     Gaz.  hebd.  de  med.,  Par. 

i860,  Gaz.  d.  hop.  Par.,  i860. 
Turin,  Blutuntersuchungen  unter  dem  Einiiuss  der  Schilddriise  und  Schilddriisen-sub- 

stanzen.     Deutsche  Ztschr.  f.  Chir.,  107,  1910. 
Ulrich,  Chr.,  Uber  Morbus  Basedowi  Myxodem.     Therap.  Monatsh,  1909,  291. 
Ungermann,  Uber  einen  Fall  von  Athyreosis  und  vikariierender  Zungenstruma.     Arch.  f. 

path.  Anat.  [etc.],  Berl. 
Unna,  Miinchen,  med.  Wchenschr.,  1896,  602. 
Vassale  and  Generali,  see  Chapter  on  Parathyroids. 
Vermehren,  Stoffwcchseluntersuchungen  nach  Behandlung  mit  Glandula  thyreoidea,  etc. 

Deutsche  med.  Wchenschr.,  255,  1893. 


THYROID    GLAND  607 

Vermorel,  De  I'origine  thyreoidienne  de  certaines  tachycardies  ou  palpations  nerveuses  de 

la  puberte  et  de  la  menopause.     Centralbl.  f.  Gynak.,  1909,  1720. 
Vigouroux,  R.,  tJber  das  Verhalten  des  galvanischen  Leitungswiderstandes  bei  der  Base- 

dowschen  Krankheit.     Centralbl.  f.  Nervenh.,  10,  1887. 
Virchow,  tJber  Myxodema.  Berl.  klin.  Wchenschr.,  1887,  121. 
Voit,  Fritz,  Stoffwechseluntersuchungen  am  Hund  mit   frischer  Schilddriise  undjodo- 

thyrin  Ztschr.  f.  Biol.,  35,  116,  1897. 
Vollmann,   tJber  einen   Fall  von  geheiltem   Myxodem  nach   Schilddriisenexstirpation. 

Inaugural  Dissertation,  Wiirzburg,  1893. 
V.  Wagner,  see  Cretinism. 

V.  Wagner  and  v.  Schlagenhaiijer,  see  Endemic  Cretinismus. 
Walter,  tJber  den  Einfluss  der  Schilddriise  auf  die  Regeneration  der  peripheren  mark- 

haltigen  Nerven.     Deutsche  Ztschr.  f.  Nervenh.,  38,  i,  1909. 
Weygandt,  tJber  Virchows  Kretinentheorie.     Neurol.  Centralbl.,  1904,  290. 
White,  Cli_fford,  A  fetus  with  congenital  hereditary  Graves'  disease.     Proc.  Roy.  Soc.  Med., 

5,  obstr.  sec,  1912,  247. 
Wiener,  H.,  Uber  den  Thyreoglobulingehalt  der  Schilddriise,  etc.     Arch.  f.  exper.  Path.  u. 

PharmakoL,  61,  1909. 
Worms  and  Hamant,  De  I'exophthalmie  unilaterale,  etc.     Gaz.  d.  Hop.,  191 2,  Nr.  70,  1639. 
Wyss,  R.  v.,  see  Endemic  Cretinism. 
Zitschmann,  Beitrag  zum  Studium  der  Folgen  der  Schilddriisenextirpation.     Mitt.  a.  d. 

Grenzgeb.  d.  Med.  u.  Chir.,  19  u.  Arch.  f.  wissensch.  u.  prakt.  Theirp.,  93,  1907. 


CHAPTER  III 

CRETINIC  DEGENERATION 

Alexander,  G.,  Das  Gehororgan  der  Kretinen.     Arch.  f.  Ohrenh.,  78,  1908,  54. 

Bayon,  Neurol.  CentralbL,  792. 

Bircher,  E.,  Ein  Beitrag  zur  Kenntnis  der  Schilddriise  and  Xebenschilddriise  bei  Kretinoi- 

den,  Kretinen  und  endemisch  Taubstummen.     Frankf.  Ztschr.  f.  Path.,  11,  262, 

1912. 

—  Fortfall  und  Anderung  der  Schilddriisenfunktion,  etc.     Ergebn.  d.  Path.  Lubarsch- 

Ostertag.,  15,  191 1. 

—  Die  Entwicklung  und  der  Bau  des  kretinen  Skelettes  im  Rontgenogramm.     Erg.,  21, 

Fortschr.,  a.  d.  Geb.  d.  Rontgenstrahlen. 

—  Zur  Pathogenese  der  Kretinoiden  Degeneration.     Berhn,  1908.     Urban  und  Schwar- 

zenberg. 

—  Zur  experimentellen  Erzeugung  der  Struma,  etc.     Deutsche  Ztschr.  f.   Chir.,  103, 

1910. 

—  Zur  Pathogenese  der  kretinischen  Degeneration.     ^led.  KHn.,  1908,  Beiheft  6.     Exper. 

Beitr.  z.  Kropfherz.  Med.  KUn.,  10,  1910. 

—  Zur  Implantation  von  Schilddriisengewebe  bei  Kretinen.     Deutsche  Ztschr.  f.  Chir., 

98,  1909. 
Bircher,  H.,  Der  endemische  Kropf  und  seine  Beziehungen  zur  Taubstummheit  und  zum 
Kretinismus.     Basel,  1893. 

—  Das  Myxodem  und  die  kretinoide  Degeneration.     Volkmanns  klin.  Vortrage,  1890, 

Nr.  3,  5,  7. 
Blum,  see  Thyroid  Gland. 
Bourneville,  see  Thyroid  Gland. 

Breitner,  Uber  Ursache  und  Wesen  des  Kropfcs.     Wien.  klin.  Wchenschr.,  1912,  82. 
Breus  and  Kolisko,  Die  pathologischen  Beckenformen.     L  Leipzig  und  Wien.,  1904, 

Deuticke. 
Coulon,  de,  Uber  Tyreoidea  und  Hypophysis  der  Kretinen,  etc.     Arch.  f.  path.  Anat. 

[etc.],  Berl.,  147,  1897,  p.  53-99. 
Cyon,  V.  see  Thyroid  Gland. 
Danziger,  Cited  by  Ewaldt. 
Dexler,  H.,  Uber  endemischen  Kretinismus  bei  Tieren.     Berl.  thierarztl.  Wchenschr., 

1909,  Xr.  21-24. 
Dieterle,  Uber  endemischen  Kretinismus.     Jahrb  f.  Kinderh.,  64,  1906. 

—  See  also  chapter  on  Thyroid  Gland. 

Eiselsberg,  v.  Die  Krankheiten  der  Schilddriise.     Stuttgart,  1901,  Encke. 

Eller,  Familiarer  Kretinismus  in  Wien.     Jahrb.  f.  Kinderh.,  71,  1910. 

Eppinger,  Sr.,  cited  by  Scholz. 

Ewald,  Die  Erkrankungen  der  Schilddriise,  Myxodem  und  Kretinismus.     II.  Aufl.  A. 

Holder,  Leipzig  u.  Wien,  1909. 
Eysselt,    v.,    Ein    Jahr    Kretinenbehandlung    mit    Schilddriisensubstanz.     Wien.    med. 

Wchenschr.,  1907,  Nr.  1-3. 

608 


CRETINIC   DEGENERATION  609 

Froschels,  E.,  tJber  die  Grlinde  der  Hor-  und  Sprachstorung  beim  Kretinismus,  etc. 

Monatschr.  f.  Ohrenh.,  45,  1912. 
Getzowa,  tJber  die  Thyreoidea  von  Kretinen,  etc.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  180, 

i9os._ 
Gutzmann,  tJber  die  Storungen  der  Stimme  und  Sprache.     Ergebn.  d.  innere.   Med.  u. 

Kinderh.,  3,  1909,  327. 
Hahermann,  /.,  Zur  Lehre  der  Ohrenerkrankungen  infolge  von  Kretinismus.     Arch.  f. 

Ohrenh.,  79,  1909,  23. 
Hanau,  X  international  Congress  at  Berlin,  2,  128. 
Hitschmann,  Augenuntersuchungen  bei  Kretinismus  und  Zwergwuchs,  etc.     Wien.  klin. 

Wchenschr.,  1898,  Nr.  27. 
Johannesen,  Verbreitung  und  Atiologie  des  Kropfes  in  Norwegen.     Ztschr.  f.  klin.  Med., 

24,  1891. 
Kocher,   Th.,   Zur  Verhiitung   des   Kretinismus   und  kretinoider   Zustande.     Deutsche 

Ztschr.  f.  Chir.,  34,  1892.     (Ref.  from  dem  Kongress  f.  innere  Medizin,  1906.) 
Kranz,  P.,  Schilddriise  und  Zahne.     Deutsche  Monatschr.  f.  Zahnheilk.,  30,  i,  1912. 
Kraus,  Fr.,  Die  Pathologic  der  Schilddriise.     Kongress  f.  innere.  Med.,  1906. 
— tJber  das  Kropfherz.     Wien.  klin.  Wchenschr.,  1899,  416. 
— tJber  Kropfherz.     Deutsche  med.  Wchenschr.,  1906,  1889. 
Kutschera,  Das  Grossenwachstum  bei  Schilddriisenbehandlung.     Wien.  klin.  Wchenschr., 

1901,  771. 
Lager,  St.,  cited  by  Bircher. 
Langhans,  Anatomische  Beitrage  zur  Kenntnis  der  Kretinen.     Arch.  f.  path.  Anat.  [etc.], 

Berl.,  149,  155,  1897. 
LohenJiofer,  Die  Verbreitung  des  Kropfes  in  Unterfranken.     Mitt.  a.  d.  Grenzgeb.  d. 

Med.  u.  Chir.,  24,  505,  1912. 
Lombroso,  cited  by  Bircher. 

Magnus-Levy,  tJber  Myxodem..     Ztschr.  f.  klin.  Med.,  52,  1904. 
Mikulicz,  V.  and  Reinbach,  tJber  Thyreoidismus.     Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir., 

8,  1901. 
Minnich,  Das  Kropfherz.     Leipzig  u.  Wien.,  Deuticke,  1904. 
Moos  and  Steinbrilgge,  cited  by  Ewald. 

Nager,  Die  Taubstummen  der  Luzerner  Anstalt  Hohenrain.     Ztschr.  f.  Ohrenh.,  43,  234. 
Ottolenghi,  II  campo  visivo  nei  cretini.     Arch,  di  Lombroso,  1893,  256.     Giornale  d.  r. 

Acad.  med.  de  Torino,  12,  1893. 
Paltauf,  A.,  see  Dwarfism,  Chapter  XII. 
Revilliod,  see  Thyroid  Gland. 

Rose,  E.,  Der  Kropftod  und  die  Radikalkur  der  Kropfe.     Arch.  f.  klin.  Chir.,  22,  1878. 
Scholz,  W.,  Klinische  und  experimentelle  Untersuchungen  iiber  den  Kretinismus.     Berlin, 

1906. 
— tJber  Behandlung  des  Kretins  mit  Schilddriisensubstanz.     Kongr.  f.  innere.  Med.,  1902. 
— tJber  das  Kropfherz.     Berl.  klin.  Wchenschr.,  9,  381,  1909. 
— tJber  den  Stoffwechsel  der  Kretinen.     Ztschr.  f.  exper.  Path.  u.  PharmakoL,   1905, 

Nr.  2. 
— Tiber  Kretinismus.     Ergebn.  d.  innere.  Med.  u.  Kinderh.,  3,  1909. 
Scholz  und  Zingerle,  Beitrag  zur  pathologischen  Anatomie  der  Kretinengehirne.     Ztschr. 

f.  Heilk.,  1906,  57. 
Schranz,  /.,  Beitrag  zur  Theorie  des  Kropfes.     Arch.  klin.  Chir.,  34,  92. 
Schroder,  Beitrag  zur  Kenntnis  des  Myxodems.     Psychiat.-neurol.  Wchenschr.,  3-5,  1907. 
Sofer,  Die  Bekampfung  des  Kretinismus  in  Osterreich.     Neurol.  Central.,  1910,  320. 
39 


6lO  LITERATURE 

Vllmann,  £.,  Uber  Beziehungen  zwischen  dem  Utersusmyom  und  dem  Kropf.     Wien. 

klin.  Wchenschr.,  1910,  Xr.  16. 
Wagner,  v.  Mittl.  d.  Ver.  der  Aerzte  in  Steiermark,  1893. 
— Uber  endemischen  und  sporadischen  Kretinismus.     Wien.  klin.  Wchenschr.,  1900,  Xr. 

19- 
Wagner,  v.,  Zur  Behandlung  des  endemischen  Kretinismus.     Wien.  khn.  Wchenschrift, 

1902,  Xr.  25. 
— tjber    Myxodem    und    sporadischen    Kretinismus.     Wien.    med.    Wchenschr.,    1903, 

Xr.  2-4. 
— Uber  marinen  Kretinismus.     Wien.  klin.  Wchenschr.,  1906,  1273. 
Wagner  v.  and  v.  Schlagenhaujer,  Beitrag  zum  endemischen  Kretinismus.     Deuticke,  1910. 
Werdt,  V.  Uber  LymphfolhkelbUdung  in    Struen.      Frankf.  Ztschr.   f.  Path.,  8,  Heft    3. 
Wolfler,  Chirurgische  Behandlung  des  Kropfes.     Berlin,  1890. 
Wyss,  R.  v.,  Beitrag  zur  Entwicklung  des  Skeletts  von  Kretinen,  und  Kretinoiden.     Fort- 

schr.  a.  d.  Geb.  d.  Rontgenstrahlen,  1899-1900,  Heft  5. 


CHAPTER  IV 

PARATHYROID  GLANDS 

Adler,  S.,  and  H.  Thaler,  Experimentelle  and  klinische  Studien  zur  Graviditatstetanie. 

Ztschr.  f.  Geburtsh.  u.  Gynaek.,  62,  194,  1909. 
Albu,  Die  Tetanie  Magenkranker.     Volkm.  Sammlung  klin.  Votr.,  1899,  Nr.  254. 
— Zur  Frage  der  Tetanie  bei  Magendilatation.     Arch.  f.  Verdauungskr.,  4,  466,  1896. 
Aran  and  Rabaud,  cited  by  v.  Frankl-Hochwart. 
Aschenheini,  E.,  tjber  den  Aschengehalt  in  den  Gehirnen  Spasmophiler.     Monatschr.  f. 

Kinderheilk.,  9,  Nr.  7. 
Ast.  Fr.,  tJber  zwei  Falle  von  Tetanie.     Deutsches  Arch.  f.  klin.  Med.,  63,  193. 
Auerbach,  P.,  Epithelkorperchenblutung  und  ihre  Beziehungen  zur  Tetanie  der  Kinder. 

Ztschr.  f.  Kinderh.,  73,  Erganzungsband. 
Bartels,  Ein  Beitrag  zur  Tetaniekatarakt.     KUn.  Monatschr.  f.  Augenh.,  1906,  374. 
Bauer,  Th.,  Das  Verhalten  der  Epithelkorperchen  bei  der  Osteomalazie.     Frankf.  Ztschr. 

f.  Path.,  7,  1911. 
Bechterew,  v.  Die  Tetanie.     Ztschr.  f.  Nervenh.,  6,  477,  1895. 
— Die  Funktionen  der  Nervenzentra.     I.  Heft,  1908,  42. 
Benediki,  Elektrotherapie.     II.  Aufl.,  1886,  612. 

Benjamins,  tJber  die  Glandula  parathyr.  Beitr.  z.  path.  Anat.  u.  Physiol.,  1902,  143. 
Berkeley  and  Beebe,  Extract  of  parathyroids.     Med.  Research,  Feb.,  1909. 
Bertelli,  Falta,  and  Schweeger.     Uber  die  Wechselwirkung  der  Driisen  mit  innerer  Sekre- 

tion.     III.  Mitt.  Ztschr.  f.  klin.  Med.,  71,  Heft  i  und  2. 
Bettmann,  Ein  Fall  von  Thomsenscher  Krankheit  mit  Tetanie.     Ztschr.  f.  Nervenh.,  9, 

331,  1897- 
Biedl,  Zur  Atiologie  der  parathyreogenen  Tetanie.     Zentralbl.   f.   d.   ges.   Physiol,   u. 

Path.  d.  Stoffwechs,  11,  191 1. 
— Innere  Sekretion.     Vorlesungen,  1902.     Wien.  Khn.,  Nr.  29,  1903. 
— ^Innere  Sekretion.     Wien,  19 10,  Urban  und  Schwarzenberg. 

Blazicek,  tJber  einige  seltene  Formen  der  Tetanie.     Wien.  klin.  Wchenschr.,  1894,  826. 
— Pseudotetanie,  vorgetauscht  durch  Hysterie.     Ibidem,  1896,  373. 
Bliss,  Raymond  W.,  Die  Untersuchungen  der  Epithelkorperchen  mit  besonderer  Beriick- 

sichtigung  ihrer  Beziehungen  zur  Sauglingstetanie.  Ztschr.  f.  Kinderh.,  2,  549. 
Boese  smdLorenz,  Kropf,  Kropf operation  und  Tetanie.  Wien.  med.  Wchenschr.,  38,  1909. 
Bouveret  and  Devic,  Recherches  cliniques  et  experim.  sur  la  tetanie  d'origine  gastrique. 

Rev.  de  med.,  12,  48,  1892. 
Canal,  Augm.  influenza  della  parathyroidei  sul  decorso  di  guariguone  delle  fratture. 

Arch,  per  le  sc.  med.,  4,  1910. 
Carnot  and  Delion,  Parathyreoiditis  tuberculeuse.     Compt.-rend.  soc.  d.  biol.,  59,  321,  21. 

Oct. 
Cattaneo,  Sul  contenuto  in  Calcio  del  sangue  nella  spasmofilia  la  pediatria,  1909. 
Ceni  und  Besta,  Proprieta  terapeutiche  specifiche  del  siero  di  sangue  di  animali  immunicati, 

etc.     Riv.  sper.  di  freniat.,  1903. 
Cheadle,  U.,  Pathology  and  treatment  of  laryngismus,  tetany,  and  convulsions.     Lancet, 

1877,  919. 

611 


6l2  LITERATURE 

Chiari,   R.   and   A.   FrohUch,    Erregbarkeitsanderung   des   vegetativen   Nervensystems 

durch  Kalkentziehung.     Arch.  f.  exp.  Path.  u.  PharmakoL,  64,  214,  1911. 
Chvostek,  sr.,  Beitrage  zur  Tetanic.     Wien.  med.  Presse,  1876,   1201;  weitere  Beitrage 

zur  Tetanic,  ibid.,  1878,  821  ff.  u.  1879,  1201  ff. 
Chvostek,  Z.,  Bemerkungen  zur  Atiologie  der  Tetanic.     Wien.  klin.  Wchcnschr.,   1905, 

969. 
— Beitrage  zur  Lehrc  von  der  Tetanie.     Ibidem,  1907,  487. 
— Myasthenia  gravis  und  Epithelkorperchen.     Ibidem,  1908,  37. 
— Diagnose  und  Therapie  der  Tetanie.     Deutsche  med.  Wchenschr.,  1909. 
— tJber  das  Verhalten  der  sensiblen  Nerven,  etc.,  bei  Tetanie.     Ztschr.  f.  khn.  ]Med.,  19, 

489,  1891. 
Claude  and  Schmiergeld,  Les  glands  a  secretion  interne  dans  I'epilepsie.     Compt.-rend. 

soc.  de  bioL,  65,  138,  1908. 
Curschmann,  H.,  Tetanie,  Pseudotetanie,  etc.     Deutsche  Zschr.  f.  Nervenh.,  27,  239  1904. 
— tJber  einige  ungewohnliche    Ursachen  und    Syndrome  der  Tetanie,   etc.     Ztschr.  f. 

Nervenh.,  39,  1910. 
• — tJber  die  idiomuskulare  Ubererregbarkeit.     Ibidem,  28,  361. 
Danielsen,  Erfolgreiche  Epitheltransplantation,  etc.     Beitr.  z.  Chir.,  66,  85,  1910. 
Eggers,  Tr.  Chicago  Path.  Soc,  1907. 

V.  Eiselsberg,  Die  Krankheiten  der  Schilddriise.     Deutsche  Chir.,  38,  1901. 
— tJber  Tetanie  im  Anschluss  an  Kropfexstirpation.     Wien,  1890. 
— Weitere  Beitrage  zur  Lehre  von  den  Folgezustanden  der  Kropfoperationen.     Beitr.  z 

Chir.  Billroth-Festschr.,  Stuttgart,  1892. 
Enderlen,  Untersuchungen  iiber  die  Transplantation  der  Schilddriisen,  etc.     Mitt.  a.  d. 

Grenzgeb.  d.  Med.  u.  Chir.,  3,  474,  1898. 
£^^i«ger,Fa//o,  andi?«(f/«ger,  UberdieWechsehvirkungderDriisen  mit  innerer  Sekretion. 

II.  Ztschr.  f.  kUn.  Med.,  67,  1900. 
Erb,  Zur  Lehre  von  der  Tetanie.     Arch.  f.  Psychiat.,  4,  271,  1874. 
Erdheim,  J.,  Morphologische  Studien  iiber  die  Beziehung  der  Epithelkorperchen  zum 

Kalkstoffwechsel.     \'.  Frankf.  Ztschr.  f.  Pathol.,  7,  295,  191 1. 
— Tetania  parathyreopriva.     Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  16,  632,  1906. 
— tJber  Epithelkorperchenbefunde  bei  Osteomalazie.     Sitzungsb.  d.  k.  Akad.  d.  Wissensch. 

Wien,  1907,  311.     Math.-naturw.  CI. 
— Morphologische   Studien  iiber   die   Beziehungen   der  Epithelkorperchen   zum   Kalk- 
stoffwechsel.    I.  Frankf.  Ztschr.  f.  Path.,  7,  176,  191 1. 
Escherich,  Th.,  Die  Tetanie  der  Kinder.     Holder,  Wien,  1909. 
Escherich,  Th.  and  v.  Wagner,  see  Escherich. 

Ewald-Jacohson,  tJber  Tetanie.     12.  Kongr.  f.  innere  Med.  S.,  298. 
Falkenberg,  Zur  Exstirpation  der  Schilddriise.     X-Kongress  f.  innere  Med.  Wiesbaden, 

1891,  502. 
Falta,  Weitere  Mitteilungen  iiber  die  Wechselwirkung  der  Driisen  mit  innerer  Sekretion. 

Wien.  khn.  Wchenschr.,  30,  1909. 
— Ein  Fall  von  Insuificience  pluriglandulaire.     Mitt.   d.   Gcsellsch.   f.  innere  Med.   u. 

Kinderh.  Wien,  1910,  24. 
Falta  and  Kahn,  Studien  iiber  Tetanie,  etc.     Ztschr.  f.  klin.  ^led.,   191 1. 
Falta,  Newburgh,  and  Nobel,  Uber  die  Wechselwirkung,  etc.     IV.  Ztschr.  f.  khn.  Med.,  72, 

191 1. 
Falta  and  Rudinger,  Klinische  und  experimentelle  Studie  iiber  Tetanie.,  226.     Kongr.  f. 

innere  INIed.  Wiesbaden,  1909. 
Feer,  Die  idiopathischen  Krampfe  (Spasmophilic)  des  frtihen  Kindesalters.     Cor.-Bl.   f. 

schweiz.  Aerzte,  1908,  Nr.  22,  714. 


PARATHYROID    GLANDS  613 

Fellner,   Uber  die  Beziehungen  innerer  Krankheiten  zu  Schwangerschaft,    Geburt  und 

Wochenbett.     Deuticke,  Leipzig  u.  Wien.,  1903. 
Ferranini,  Histologische  Veranderungen  des  Zentrabiervensystems  und  des  !Magens  bei 

Tetanie  des  INIagens.     Zentralbl.  2.  innere  IMed.,  1901,  i. 
Finkelstein,  H.,  Jahrb.  d.  Sauglingskr.,  I..  2.,  Teil.  S.,    239. 
Fleiner,  Uber  Neurosis  gastrischen  Ursprungs.     Arch.  f.  Verdauungskr.,  i,  u.  5. 
— Xeue  Beitrage  zu  der  Jetanie  gastrischen  Ursprungs.     Deutsche  Ztschr.  f.  Xervenh., 

18,  243,  1900. 
- — Uber  Tetania  gastrica.     INIlinchen.  nied.  "Wchenschr.,  1903,  Xr.  10  u.  11. 
Fleischmann.  L.,   Die  Ursache   der   Schmelzhypoplasien.     Oesterr.-ungar.   Vrtljschr.   f. 

Zahn.,  25,  1909. 
Fraisseix,  Goitre  exopht.  et  Tetanie.     These  de  Paris,  1900. 
Frankl-Hochwart,  v.,  Die  Tetanie.     II.  Aufl.  Wien,  1907,  Holder. 
— Die  Prognose  der  Tetanie  der  Erwachsenen.     XeuroL  Centralbl.,  14,  u.  15,  1906. 
Freund,  E.,  Uber  die  Beziehungen  der  Tetanie  zur  Epilepsie  und  Hysteric,  etc.     Deutsches 

Arch.  f.  klin.  Med.,  76,  1903. 
Freund,  H.,  Zwei  seltene  Falle  von  Tetanie.     Miinchen  med.  Wchenschr.,  1898,  Xr.  39. 
Fries,  Wien.  klin.  Wchenschr.,  1907,  150. 
Frohlich,  A.  and  O.  Loeun,  Scheinbare  Speisung  der  Xervenfaser  mit  mechanischer  Erreg- 

barkeit  seitens  ihrer  Xervenzelle.     Centralbl.  f.  Physiol.,  21,  Xr.  9. 
Fuchs,  A.,  Wien.  med.  Wchenschr.,  191 1,  Xr.  29-31. 
— Die  Messung  der  Pupillengrosse.     Wien,  1904,  120. 
Ganghofner,  Ztschr.  f.  Kinderh.,  12,  1891,  u.  1901. 

Garre,  Epithelkorperchentransplantation.     Verhandl.  d.  deutsch.  Gesellsch.  f.  Chir.,  1908. 
Gerhardt,  Mitteil.  in  der  GeseUsch.  der  Charitearzte.     Berl.  khn.  Wchenschr.,  36,  1886. 
Gley,  Sur  les  effets  de  I'extirpation  du  corps  th}T:eoid.     Compt.  rend.  soc.  de  bioL,  1891,  u. 

Arch.  d.  Phj^siol.  norm.  u.  path.,  1892,  1893  u.  1897. 
Grosser,  P.  and  R.  Petke,  Epithelkorperchenuntersuchungen  mit  besonderer  Beriicksichti- 

gung  der  Tetania  infantum.     Ztschr.  f.  Kinderh.,  i,  458. 
Haherfeld,  Die  Epithelkorperchen  bei  Tetanie,  etc.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  203, 

283,  1911. 
Haberfeld,  W.  and  P.  Schilder,  Die  Tetanie  des  Kaninchens.     INIitt.  a.  d.  Grenzgeb.  d. 

Med.  u.  Chir.,  20,  1909. 
Eagenbach,  Exper.  Studie  iiber  die  Funktion  der  Schilddriise  und  der  Epithelkorperchen. 

Mitt.  a.  d.  Grenzgeb.  d.  INIed.  u.  Chir.,  18,  1907. 
Halstead,  W.  S.,  The  transplantation  of  parath}Toid  glands  in  dogs.     Proc.  Path.  Soc, 

Phila.,  und  J.  Exper.  M.,  5,  74,  1908,  and  Auto-  and  iso-transplantation  in  dogs 

of  the  parathjToid  glandules.     J.  Exper.  M.,  11,  175,  1909. 
Hanke,  V.,  Cataract,  Xeuritis  optica,  Degeneration  des  Pigmentepithels  der  Irishinter- 

flache  bei  Tetanie.  24.  Versannul  d.  Ophthalm.  Gesellsch.  Heidelberg,  1908,  329. 
Hecker,  Gesellsch.  f.  Xaturheilk.  in  Dresden.  Miinchen.  med.  Wchenschr.,  1906,  2225. 
Hirsch,   R.,    Glykosurie  nach   Schilddrlisenextirpation  bei  Hunden.     Ztschr.   f.   exper. 

Path.  u.  Therap..  3. 
Hirschl,  Wien.  klin.  Wchenschr.,  1904,  608. 

Hoffmann,  Deutscher.  Arch.  f.  khn.  INIed.,  43,  109,  1888.     (Fall  13.) 
• — Zur  Lehre  von  der  Tetanie.     Arch.  f.  path  Anat.  [etc.],  Berl.,  43,  ^s,  1888. 
Eorsley,  V.,  Die  Funktion  der  Schilddriise,  etc.     Festschr.  f.  Virchow  I.,  Berhn,  1891. 
Hulst,  Ein  Tumor  der  Gland.  parath>T.     Centralbl.  f.  allg.  Path.  u.  path.  Anat.,  16,  103. 
Ibrahim  I.,  Uber  Tetanie  der  Sphinkteren  der  glatten  IMuskeln  und  des  Herzens  bei 

Sauglingen.     Deutsche.  Ztschr.  f.  Xervenh.,  41,  191 1. 
Iddo  and  Sarles.  cited  by  Mac  Callum  und  Vogtlin. 


6 14  LITERATURE 

Iselin,  H.,  Tetanic  jugendlicher  Ratten,  etc.     Deutsche  Zeitschr.  f.  Chir.,  93,  397,  1908. 
Jacobi,  Struma  und  Tetanie.     Wien.  klin.  Wchenschr.,  768,  1904  und  Ztschr.  f.  Nerven- 

heilk.  32,  1907. 
Jakscii,  v.,  Klinische  Beitrage  zur  Tetanie.     Ztschr.  f.  khn.  Med.,  1890. 
Jeandelize,  Insuffisance  thyreiodienne  et  parathyreiodienne.     These  de  Nancy,  1902. 
Jorgeiisen,  G.,  Uber  die  Bedeutung  der  pathologisch-anatomischen  Veranderungen  der 

Glandulae  parathyreoidae.     Monatschr.  f.  Kinderh.,  10. 
Kasliida,  K..  Uber  Tetanie.     ]\Iitth.  a.  d.  med.  Fac.  d.  k.  jap.  Univ.,  Tokio,  5,  1904, 

Heft  3. 
Kasparek,   Ein  Fall  von  Tetanie  mit   Intentionskriimpfen.     Wien,   klin.   Wochenschr., 

1890,  850. 
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Kocher,  T/i.,  Referat  on  die  Schilddriise.     Kongr.  f.  innere  Med.,  1906. 
Konigstein,  Wien.  klin.  Wchenschr.,  1906,  779. 
Koeppe,  Monatschr.  f.  Kinderh.,  6,  510. 

Kohn,  Die  Epithelkorperchen.     Ergebn.  d.  Anat.  u.  Entwicklungsgesch.     1899  u.,  1900. 
Krabbel,  Zur  Behandlung  der  Tet.  parathyreopr.,  etc.     Beitr.  z.  klin.  Chir.,  72,  505, 

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Kraepeli)!,  Zur  Myxodemfrage.     Neurol.  Centralbl.,  3,  71,  1890. 
Krajewska,  La  tetanie  des  femmes  osteomalac.     16.  Internat.  med.  Congr.  11,  Budapest, 

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Kukciii.  Ein  Fall  von  latenter  Tetanie  bei  hochgradiger  Erweiterung  des  jVIagens  infolge 

karzinomatoser  Pylorusstenose.     Berl.  klin.  Wchenschr.,  1898,  989. 
Kunn,   Uber  Augenmuskelkrampfe  bei  Tetanie.     Deutsche   med.     Wochenschr.,    1897, 

Nr.  26. 
Knssmaid,  Uber  die  Behandlung  der  IMagenerweitcrung  durch  eine  neue  INIethode  mittelst 

der  Magenpumpe.     Deutsches  Arch.  f.  klin.  ]\Ied.,  6,  481,  1869. 
Lanz,  Cachexia  und  Tetania  thyreopriva.     Centralbl.  f.  Chir.,  1905,  339  und  Volkmanns 

klin.  \'ortrage,  87. 
LeiscJuier   and    Ko/ilcr,    Uber   homoioplastische    Epithelkorperchen-    und    Schilddrusen- 

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Leopold  and  v.  Rciiss,  Uber  die  Beziehungen  der  Epithelkorperchen  zum  Kalkbestand 

des  Organismus.     Wien.  klin.  Wchenschr.,  1908,  1343. 
Levi,  Riv.  crit.  de  med.,  1906,  Nr.  39. 
Loeb,  Arch.  f.  d.  ges.  Physiol.,  91,  248,  1902. 
Lowental  and  Wiebrecht,  Uber  die  Behandlung  der  Tetanie  mittels  Nebenschilddriisen- 

praparaten.     Deutsche  Ztschr.  f.  Nervenh.,  31,  414,  1906. 
Lundborg,  Spielen  die  Glandulae  parathyreoideae  in  der  menschlichen  Pathologic  eine 

Rollc?     Deutsche  Ztschr.  f.  Nervenh.,  27,  217,  1904  und  Centralbl.  f.  Nervenh. 

in  Psychiat.,  1905. 
MacCallum,  Die  Bezichung  der  Parathyroiddriisen  zur  Tetanie.  Centralbl.  f.  allg.     Path., 

76,  385,  1905. 
MacCallum  and    Voegtlin,   On  the  relation  of  tetany  to  the  parathyroid  glands  and  to 

calcium  metabolism.     J.  exper.  M.,  11,  1909. 
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1883. 


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Mager,  Uber  das  Fazialisphanomen  bei  der  Enteroptose.     Wien.  klin.  Wchenschr.,  1906, 

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Marburg,  0.,  Zur  Path,  der  Myasthenia  gravis.     Ztschr.  f.  Heilk.,  28,  no,  1907. 
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see  also  Pathologie  der  Linse,  Lubarsch-Ostertag.     Ergebnisse.  ]\Iorph.  u.  Path. 

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Pfeiffer.  H.  and  0.  Meier.  Experimentelle  Beitrage  zur  Kenntnis  der  Epithelkorperchen- 

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Pineles,  P.,  Klinische  und  experimentelle  Beitrage  zur  Phj^siologie  der  Schilddriise  und  der 

Epithelkorperchen.     ]\Iitt.  a.  d.  Grenzegeb.  f.  Med.  u.  Chir..  14,  1904. 
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113,  1904  und  117,  1908. 


6i6  LITEEATURE 

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— Tetaniestar,  etc.     Wien.  klin.  Wchenschr.,  iqo6,  691. 

— Zur  Pathogenese  der  Kindertetanie.     Jahrb.  f.  Kinderh.,  66,  1907. 

— Behandlung  der  Tetanie  mit  Epithelkorperchenpraparaten.     Arb.  a.  d.  neurol.     Inst. 

Wien,  1907. 
— tjber  parathyreogenen  Laryngospasmus.     Wien.  klin.  Wchenschr.,  1908,  643. 
Pirquet,  v.,  Die  anodische  Ubererregbarkeit  der  Sauglinge.     Wien.   med.   Wchenschr., 

1907,  Nr.  I. 
Pool,  Tetany  parathyreopriva.     Ann.  Surg.,  Oct.,  1907. 
Popper,  Dyspnoe  bei  Tetanie.     Arch.  f.  Kinderh.,  18,  198,  1895. 
Popetschnigg,  Cited  by  Eschcrich. 

Proescher,  F.  and  Th.  Diller,  A  fatal  case  of  tetany  with  autopsy  findings  showing  hemor- 
rhages in  the  parathyreoid  glands.     Am.  J.  Med.  Sc,  143,  696,  191 2. 
Quervain,  F.  de,  tJber  Veranderungen  des  Nervensystems  bei  experimenteller  Cachexia 

thyreopriva.     Arch.  f.  path.  x\nat.  [etc.],  Berl.,  133,  1893. 
Quest,  Jahrb.  f.  Kinderh.,  61,  114.     1905  und  Wien.  klin.  Wochenschr.,  1906,  830. 
Redlich,  E.,  Tetanie  und  Epilepsie.     Monatschr.  f.  Psychiat.  u.  Neurol.,  30,  4,  39.     191 1. 
Rosenstern,  Kalzium  und  Spasmophilic.     Jahrb.  f.  Kinderh.,  72,  2. 
Roussy  and  Climet,  Les  parathyreoidcs  dans  4  cas  de  M.  dc  Parkinson.  Compt.  rend.  soc. 

de  biol.,  7,  1910. 
Rudinger,  C,  Zur  Atiologie  und  Pathologic  der  Tetanie.     Ztschr.  f.  exper.   Path.  u. 

Pharmakol.,  5,  1908. 
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1909. 
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Wien.  klin.  therap.  Wchenschr. 
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Saiz,  Giov,  Beitrag  zum  Vorkommen  und  zur  Behandlung  der  Tetanie.     Wien.  klin. 

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Ztschr.  f.  Nervenh.,  25,  i,  1904. 
Schif,  M.,  Bericht  iiber  cine  Versuchsreihe  bctr.  die  Wirkungcn  der  Exstirpation  der 

Schilddriisc.     Arch.  f.  exper.  Path.  u.  Pharmakol.,  18,  1884. 
Schlesinger,  H.,  Ein  bisher  unbekanntcs  Symptom  bei  der  Tetanie  (Beinphiinomen). 

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40,  1910. 
Schreiber,  L.,  Beitrage  zur  Kenntnis  der  Entwicklung  und  des  Baues  der  Gl.  parathyr. 

Arch.  f.  mikr.  Anat.,  52,  1908. 
Schiiller,  Rachitis  tarda  and  Tetanic.     Wien.  med.  Wchenschr.,  1909. 
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einem  Individuum.     Wien.  khn.  Wchenschr.,  1896,  5. 
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CHAPTER  \' 

THYMUS 

Avion,  G.,  Uber  den  Thymustod.     Wien.  klin.  Wchenschr..  191 2.  Xr.  27. 
Bang,  Ivar,  Chemische  Untersuchungen  der  lymphatischen  Organe.     Beitr.  z.  chem.  Phy- 
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Basch,  Die  Beziehung  der  Thymus  zum  Xervens^'stem.     Jahrb.  f.  Kinderh.,  58,  1908. 
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Biedl,  Innere  Sekretion.     Wien,  Urban  u.  Schwarzenberg,  1910. 
Bircher,  Fortfall  und  Anderung  der  Schilddriisenfunktion  als  Krankheitsursache.     Lub- 

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Bischoff,  Th.,  Entwicklungsgeschichte  der  Saugetiere  und  des  Menschen.     Leipzig,  1842. 
Bourneville,  Comparaison  antra  las  enfants  normaux  at  las  anfants  anormaux  au  point  de 

vue  de  la  persistance  ou  de  I'absence  du  thymus.     Progres  med..  29,  389,  1900. 
Bramwell,  A  case  of  intrathoracic  tumor  (lymphosarcoma)  with  secondary  deposit  in  the 

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Calzolari,  Recherches  experiment,  sur  un  rapport  probable  entre  la  fonction  du  thymus  et 

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Clark.  A  case  of  absence  of  the  thymus  gland  in  an  infant.     Lancet.  74,  1077,  1896. 
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V.  Ghika,  Etude  sur  le  thymus.     These  de  Paris,  1901. 
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188.  Xr.  22. 
Hammar,  Zur  groberen  ^Morphologic  und  Morphogenie  der  Menschenthymus.     Anat. 

Hefte,  43,  203,  191 1. 
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Anat.  u.  Physiol.  SuppL,  1906,  91. 
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Hammer,  Uber  Thymuserkrankungen  und  Thymustod.     Inaug.-Diss.  Freiburg.  1903. 
Hart,  Uber  Thymuspersistenz  und  apoplektiformen  Thymustod,  etc.,  Miinchen.  med. 

Wchenschr.,  1908,  669  u.  744. 
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12,  321  u.  f.,  1909. 
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klin.  Wchenschr.,  1910,  814. 
Hendersson,  On  the  relationship  of  the  thymus  to  the  sexual  organs.     J.  Physiol.,  31,  1904. 
Hedinger,  E.,  Mors  thymica  bei  X'eugeborenen.     Jahrb.  f .  Kinderh..  63,  1006  and  Deutsches 

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Hinrichs,  Behinderung  der  Atmung  und  der  X'ahrungsaufnahmc  durch  eine  zu  grosse 

Thymus  bei  einem  10  jahrigen  Kinde,  Operation.  Heilung.     Inaug.-Diss.,  Leipzig, 

1907. 

618 


THYMUS  619 

Eis,  Uber  den  Sinus  praecervicalis  und  liber  die  Thymusanlage.     Arcii.  f.  Anat.  u.  Phy- 
siol., 1886.     Anat.  Abt.,  421. 
Jonson,  Studien  iiber  die  Thymusinvolution;  die  alizidentelle  Involution  bei  Hunger. 

Arch.  f.  mikr.,  Anat.,  73,  390,  1909. 
Katz,  Quelques  recherches  sur  le  thymus  chez  I'enfant.     Progres  med.,  29,  385,  1900. 
Klose  and  Vogt,  Klinik  und  Biologic  der  Thymusdriise.     Tubingen,  1910. 
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Kopp,  Denkwiirdigkeiten  der  arztlichen  Praxis.     Frankfurt  a.  M.,  1838. 
V.  Kundrat,  Zur  Kenntnis  des  Chloroformtodes.     Wien.  klin.  Wchenschr.,  1895,  Nr.  1-4. 
Langerhans  and  Saveliew,  Beitrage  zur  Physiologic  der  Thymusdriise.     Arch.  f.  path. 

Anat.  [etc.],  Berl.,  134,  344,  1893. 
Maximow,  Untersuchungen  iiber  Blut  und  Bindegewcbe.     II.  tjber  die  Histogenese  der 

Thymus  bei  Saugetieren.     Arch.  f.  mikr.  Anat.,  7  u.  74,  1909. 
Marburg,  Zur  Pathologic  der  Myasthenia  gravis.     Ztschr.  f.  Kinderheilk.,  28,  no,  1907. 
Matti,  H.,  Untersuchungen  iiber  die  Wirkung  experimenteller  Ausschaltung  der  Thymus- 
driise, etc.     Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  24,  665,  1912. 
Myers,  Congenital  laryngeal  stridor  apparently  due  to  an  enlarged  thymus  gland,  etc. 

Arch.  Pediat.,  25,  607,  1908. 
Ndgeli,  Blutkrankheiten.     Leipzig,  1907. 
V.  Neusser,  Zur  Diagnose  des   Status   thymico-lymphaticus.     Klin.   Symptomatol.   u., 

Diagn.,  191 1,  Heft  4. 
Ortner,  Zur  Klinik  der  Angiosklerose,  etc.     Wien.  klin.  Wchenschr.,  1902. 
Paltauf,  A.,  tJber  die  Beziehungen  der  Thymus  zum  plotzlichen  Tod.      Wien.   klin. 

Wchenschr.,  1889,  Nr.  46  u.  1980,  Nr.  9. 
Pappenheimer,  A  contribution  to  the  normal  and  pathological  histology  of  the  thymus 

gland.     J.  med.  Research,  22,  i,  igio. 
Paton,  The  relationship  of  the  thymus  to  the  sexual  organs.     J.  Physiol.,  32,  1904. 
Paton  and  Goodall,  Contribution  to  the  physiology  of  the  thymus.     J.  Physiol.,  31,  49, 

1904. 
Perrin,  Mort  brusquedeneuf  fils  d'  un  alcoholique.     Ann.  de  med.  and  chir.  in.,  1903,  217. 
Popper,  tJber  die  Wirkungen  des  Thymusextraktes.     Sitzungsbr.  d.  k.  Akad.  d.  Wissench. 

in  Wien,  math.-naturw.  cL,  114,  539,  1905  und  115,  201,  1906. 
Pott,  tJber  Thymusdriisenhyperplasie  und  die  dadurch  bedingte  Lebensgefahr.     Jahrb. 

f.  Kinderh.,  34,  118,  1892. 
Purrucker,  Zur  Pathologic  der  Thymusdriise.     Miinchen.  med.  Wchenschr.,  1899,  943. 
Rachford.     The  X-ray  treatment  of  Status  lymphaticus,  etc.     Am.  J.  M.  Sc,  140,  550, 

1910. 
Ranzi  and  Tandler,  tJber  Thymusexstirpation.     Wien.  klin.  Wchenschr.,  27,  1909. 
Rehn,  L.,  Trachealstenose  und  Thymustod.     Arch.  f.  klin.  Med.,  80,  468,  1906. 
Ribadeau  and  Weil,  Sur  un  cas  d'hypertrophie  du  thymus.     Bull,  et  mem.  Soc.  med  d.  hop. 

de  Par.,  28,  431,  1912. 
Ronconi,  Comportamento  del  timo  nell'uomo  nelle  varie  eta  della  vita,  etc.     Path.  Riv. 

quindicin.  Genova  anno,  i,  595,  1909. 
Schnitzler,  Wien.  klin.  Wchenschr.,  1894,  371. 

Schriddle,  Thymus.  Handb.  d.  path.  Anat.,  issued  by  Aschoff,  2,  139,  1909. 
Sommer  and  Florcken,  Uber  die  Funktion  der  Thymus.     Sitzungsbr.  d.  physiol.-med., 

Gesellsch.,    Wiirzburg,  1908,  45. 
Stieda,  Untersuchungen  iiber  die  Entwicklung  der  Glandula  thymus.     Leipzig,  1881. 
Stohr,  tJber  die  Natur  der  Thymuselemente.     Anat.  Hefte,  31,  409,  1906. 
V.  Sury,  Uber  die  fraglichen  Beziehungen  der  sog.      J\Iors  thymica  zu  den   plotzlichen 


620  LITERATURE 

Todesfallen  im  Kindesalter.     Vrtljschr.  f.  d.  ges.  ]Med.,  36,  1908,  Anat.  Hefte, 
95,  1906. 
Svehla,  Uber  die  Einwirkung  des  Thymussaftes,  etc.     Wien.  med.  BL,  1896. 

—  RoUe  der  Thymusdriise  und  innere  Sekretion  der  Thymus.     ZMiinchen.  med.  Wchen- 

schr.,   1 90c. 
Tarulli  and  Lo  Monacco,  SuUi  effeti  dell'  estirpatione  del  timo.     IX.  Congr.  intern,  med., 

Roma  Fisiol.,  2,  19,  1894. 
Wiesel,  /.,  Zur  Pathologic  dcs  chromaffinen  Systems.     Arch.  f.  path.  Anat.  [etc.],  Berl., 

176,  103,   1904. 

—  Pathologie  der  Thymus.     Lubarsch-Ostertag  Ergebnisse,  15,  416,  1912. 
Winsloiv,  Exposition  anatomique  de  la  structure  du  corps  humain.     Amsterdam,   1732. 


CHAPTER  VI 

HYPOPHYSIS 

Arnold,  I.,  Beitr.  zur  Akromegaliefrage.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  135,  i,  1894. 
Aschner  and  Forges,   Uber   den   respiratorischen   Stoffwechsel  hypophysipriver   Tiere. 

Biochem.  Ztschr.,  39,  200,  1912. 
Aschner,  B.,  tjber  einen  Fall  von  hypoplastischem  Zwergwuchs  mit  Graviditat  nebst 

Bemerkungen  liber  die  Atiologie  des  Zwergwuchs.     Monatschr.  f.  Geburtsh.  u. 

Gynaek,  32,  644,  1910. 

—  tJber  die  Funktion  der  Hypophyse.     Arch.  f.  d.  ges.  Physiol.,  146,  1912  und  Wien. 

klin.  Wchenschr.,  191 2. 

—  Demonstration  hypophysektomierter  Hunde.     Wien.  klin.  Wchenschr.  Dez.,  1909. 
Axenfeldt,  Sehnervenatrophie  undMenstruationsstorung.   Deutsche  med.   Wchenschr., 

1903;  Neurol.  Centralbl.,  1903,  608. 
Bab,  Pituitrin  als  gynakologisches  Styptikum.     Miinchen.  med.  Wchenschr.,  1911,  1554. 
Bab,  tJber  die  Behandlung  der  Osteomalazie  mit  Hypophysenextrakten.     Wien.  klin. 

Wchenschr.,  191,  Nr.  27,  997. 
Babinski  and  OnanoJ,  Tumeur  du  corps  pituitair.     Rev.  neuroL,  8,  531,  1900. 
Babonneix,  Deformations  du  type  acromegalique  chez  un  jeune  homme  de  17  ans.     Gaz. 

d.  Hop.,  1911,  Nr.  70,  1077. 
Babonneix,  L.  and  Paisseau,  G.,  Sur  quelque  cas  d'obesite,  infantile.     Gaz.  d.  Hop.,  13, 

Sept.,  1910. 
Bartels,  M.,  tJber  Plattengeschwiilste  der  Hypophysengegend.     Ztschr.  f.  Augenh.,  16, 

1906. 
Becker,  Vorstellung  von  Nervenkranken.  Neurol.  Centralbl.,  i,  505,  1894. 
Beclere,  Le  Radio-Diagnostic  de  I'Acromegalie.     Presse  med.  Paris,  98,  845,  1903. 
Benda,    C,   Beitrage   zur   normalen   und  pathologischen  Histologic   der   menschlichen 

Hypophysis  cerebri.     Berl.  klin.  Wchenschr.,  1900,  1205. 

—  tJber  vier  Falle  von  Akromegalie,  Deutsche  med.  Wchenschr.,  1901. 

—  Die  Akromegalie.     Deutsche  Klinik  HI,  1903. 

—  Path.  Anat.  der  Hypophyse.  Handb.  d.  Path.  Anat.  des  Nervensystems.     Berlin, 

1904. 
Benedict,  G.  and  John  Homans,  The  metabolism  of  the  hypophysectomized  dog.     J.  Med. 

Research,  25,  Nr.  3,  191 2. 
Bernstein  and  Falta,  tJber  die  Einwirkung  von  Adrenalin,  Pituitrinum  infundibulare  und 

Pituitrinum  glandulare  auf  den  resp.  Stoffwechsel.     Kongr.  f.  innere  Med.,  1912. 

(Work  in  detail  not  yet  published.) 
Berger,  A.,  Ein  Fall  von  Tumor  der  Hypophysengegend  mit  Obduktionsbefund.     Ztschr. 

f.  klin.  Med.,  54,  1904. 
Bertelli,  Falta,  and  Schweeger,  Uber  die  Wechselwirkung  der  Driisen  mit  innerer  Sekre- 

tion  HI.     tJber  Chemotaxis.     Ztschr.  f.  klin.  Med.,  Nr.  71. 
Biedl,  Innere  Sekretion.     Urban  u.  Schwarzenberg,  Wien,  1910. 
Bolaffio  and  Tedescho,  see  Falta,  Wietere  Beitrage  iiber  die  Wechselwirkung  der  Driisen 

mit  innerer  Sekretion.     Wien.  klin.  Wchenschr.,  1909,  Nr.  30. 
Bonnes,  L.  J.,  Consideration  sur  deux  cas  d'  acromegalic.     These  de  Bordeaux,  1907. 

621 


62  2  LITERATURE 

Bondi,  S.,  Ein  Fall  von  Osteomalazie  beim  Manne.     Gesellsch.  f.  innere  INIed.  u.  Kinderh., 

Nov.,  1910. 
Borchardt,  Z,.,  tjber  das  Blutbild  bei  Erkrankungen  der  Driiscn  mit  innerer   Sekretion, 

etc.     Deutsches  Arch.  f.  klin.  Med.,  106,  182,  191 2. 

—  Funktion  und  funktionelle  Erkrankungen  der  Hypophyse.     Ergebn.  f.  inneren  Med. 

u.  Kinderh.,  3,  1909. 

—  Die  Hypophysenglykosurie  und  ihre  Beziehung  zum  Diabetes  bei  der  Akromegalie. 

Ztschr.  f.  klin.  Med.,  1908,  Nr.  66,  332. 
Bouniier,  R.,  Tumeur  der  I'hypophyse,  etc.     Presse  med.  25,  Nov.,  1911,  973. 
Bregmann  and  Steinhans,  Zur  Kenntnis  der  Geschwiilste  der  Hypophyse  und  der  Hypo- 

physengegend.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  188,  360,  1907. 
Breuning,  Wiirzburger  Abhandlungen,  1909. 

Breus  and  Kolisko,  Die  pathologischen  Beckenformen.     Wien,  1900. 
Brisseau,  see  Launois  and  Roy. 
Buday  and  Jancso,  Ein  Fall  von  pathologischem  Riesenwuchs.     Deutsches  Arch.   f. 

kHn.  Med.,  60,  1898. 
Bychowski,  Deutsche  med.  Wchenschr.,  1909,  1561. 
Cagnetto,  G.,  Zur  Frage  der  anatomischen  Beziehung  zwischen  Akromegalie  und  Hypop- 

hysistumor.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  176,  115,  1904,  u.  187,  197,  1907. 
Claude,  H.,  Syndromes  d'hyperfonctionnement  des  glandes  vascularies  sanguines  dans 

les  acromegalics.     Compt.  rend.  soc.  d.  biol.,  57,  362,  1905. 
Claude  and  Goiigerot,  Sur  I'insuffisance  simultanee  de  plusieurs  glandes  a  secretion  interne. 

Compt.  rend.  soc.  de  biol.,  63,  785,  1907. 
Cushing,    Harvey,  The  pituitary  body  and  its  disorders.     J.  B.  Lippincott,  Philadelphia 

and  London,  1910. 

—  Die  Hypophysis  cerebri,  etc.     J.  Am.  M.  Ass.,  Nr.  53,  1909,  249. 

Cushing  and  Goetsch,  Concerning  the  secretion  of  the  infundibular  lobe,  etc.  Am.  J. 
Physiol. 

V.  Cyan,  Gefassdriisen,  1910,  124. 

V.  Dallemagne,  3  cas  d'acromcgalie.     Arch,  de  med.  exp.  et  d'anat.  path,  [etc.],  7,  589,  1895. 

Dalton,  Tr.  Path.  Soc,  London,  1897,  1106. 

Delille,  A.,  L'hypophyse  et  la  medication  d'hypophyse,  Paris,  1909. 

Demmer,  Demonstration  Gesellsch.  d.  Aerzte  Wiens.     Wien.  klin.  Wchenschr.,  191 1,  8. 

Dercum  and  MacCarthy,  Autopsy  in  a  case  of  adiposis  dolorosa.  Am.  J.  M.  Sc,  1902, 
994. 

Dietrich,  Knochen  und  Gelenkveranderungen  bei  Akromegalie.  Verhandl.  d.  deutsch. 
path.  Gesellsch.,  1909,  78. 

Doebhelin,  Pseudoakromegalie  und  Akromegalie.     Inaug.-Diss.,  Konigsberg,  1895. 

V.  Eiselsherg,  Uber  operative  Behandlung  der  Hypophysentumoren.  Wien.  klin.  Wchen- 
schr., 1907. 

V.  Eiselsherg  and  v.  Frankl-Hochwart,  Operative  Behandlung  der  Tumoren  der  Hypophy- 
sisgegend.     Neurol.  Centralbl.,  1907,  Nr.  21. 

Neuer  Fall  von  Hypophysisopcration  bei  Degeneratio  adiposo-genitalis.     Wien. 

klin.  Wchenschr.,  1908. 

Eppinger,  Falta,  and  Rudinger,  tJber  die  Wechsehvirkung  der  Driiscn  mit  innerer  Sekre- 
tion.    I.  Ztschr.  f.  klin.  Med.,  66,  i,  1908. 

Erh,  cited  by  Pel. 

Erdheim,  Hypophyscngangsgeschwiilste.  Sitzungsbr.  k.  Akad.  d.  Wisscnsch.  Wien. 
Mat.-natur.  CI.  Abt.,  Ill,  113,  1904. 

—  tJber  einen  Hypophysentumor  von  ungewohnlichem  Sitz.     Beitr.  z.  path.  Anat.  u. 

Physiol.,  46,  233,  1909. 


HYPOPHYSIS  623 

Erdheim  and  Shimme,  tjber  die  Schwangerschaftsveranderung  der  Hypophyse.     Beitr. 

2.  path.  Anat.  u.  Physiol.,  46,  1909. 
Exner,  Beitrage  zur  Pathologic  und  Pathogenese  der  Akromegalie.     Mitt.  a.  d.  Grenz- 

geb.  d.  Med.  u.  Chir.,  20,  1909. 

—  Operation  bei  Akromegalie.     Gesellsch.  d.  Aertze  in  Wien.     Wien.  klin.  Wchenschr., 

1909,  Nr.  3. 
Falta,  Mitteil.  d.  Gesellsch.  f.  inn.  Med.  u.  Kinderh.  Wien,  2,  24,  191c. 

—  Concerning  diseases  that  depend  on  disturbances  of  internal  secretion.     Am.  J.  M. 

Sc,  April,  1909. 
Falta  and  Kahn,  Klinische  Studien  iiber  Tetanie  mit  besonderer  Beriicksichtigung  des 

vegetativen  Nervensystems.     Ztschr.  f.  klin.  Med.,  74,  Heft  i  u.  2. 
Falta,  W.,  and  Priestley,  G.  B.,  Beitrage  zur  Regulation  von  Blutdruck  und  Kohlehydrat- 

stofTwechsel  durch  das  chromaffine  System.     Berl.  klin.  Wchenschr.,   1911,  Nr. 

47- 
Falta  and  Nowaczynski,   T.,   tJber  die  Harnsaureausscheidung  bei  Erkrankungen  der 

Hypophyse.     Berl.  klin.  Wchenschr.,  1909,  Nr.  38. 
Falta,  Newhurgh,   and  Nobel,   tJber  Beziehungen  der  tjberfunktion  zur   Konstitution. 

Ztschr.  f.  klin.  Med.,  72,  Heft  i  u.  2. 
Falta  and  locovic,  ProtokoU  der  k.  k.  Gesellsch.  d.  Aertze  Wien.     Wien.  klin.  Wchenschr., 

17,  Dez.,  1909. 
Fazio,  Sopra  un  caso  d'acromegalie.     Riforma  med.  II,  1896,  399. 
Fischer,  B.,  Hypophyse,  Akromegalie  und  Fettsucht.     Wiesbaden,  Bergmann,  1910. 
Foges,  A.  L.,  and  Hofstdtter,  R.,  tJber  Pituitrinbehandlung  bei  post-partum  Blutungen. 

Centralbl.  f.  Gynak.,  1910,  Nr.  46. 
Formanek,  Zur  Kasuistik  der  Hypophysengangsgeschwulste.     Wien.  klin.  Wchenschr., 

1909,  603. 
Forschhach  and  Weber,  Beobachtungen  uber  die  Harn-  und  Salzausscheidung  im  Diabetes 

insipidus.     Ztschr.  f.  klin.  Med.,  73,  221. 
Franchini,  G.,   Beitrag  zum   chemischen  und   histologischen   Studium  des   Blutes  bei 

Akromegalie.     Berl.  klin.  Wchenschr.,  1908,  Nr.  36. 
Franchini  and  Giglioli,  Encore  sur  I'acromegalie.     N.  Iconog.  de  la  Salpetriere,  21,  325, 

1908. 
Frank,   E.,   tJber   Beziehungen   der   Hypophyse   zum   Diabetes   insipidus.     Berl.   klin. 

Wchenschr.,  1912,  393. 
Frankl-Hochwart  v..  Die  Diagnostik  der  Hypophysentumoren  ohne  Akromegalie.     16 

intern,  med.  Kongr.  Budapest,  1909. 
Frankl-Hochwart  v.,   and  Frohlich,   Zur   Kenntnis   der  Wirkung   des   Hypophysins   auf 

das  sympathische  und  autonome  Nervesystem.     Arch,  f .  exper.  Path.  u.  PharmakoL, 

63*  347,  1910- 
Frdnkel,  Stadelmann,  and  Benda,  Klinische  und  anatomische  Beitrage  zur  Lehre  von  der 

Akromegalie.     Deutsche  med.  Wchenschr.,  1901,  513. 
Frdntzel,  tJber  Akromegalie.     Deutsche  med.  Wchenschr.,  1888,  32. 
Freund,  H.  W.,  tJber  Akromegalie.     Volkmanns  klin.  Vortrage,  1889,  Nr.  329. 
Fritsche  and  Klehs,  Beitrage  zur  Pathologic  des  Ricsenwuchses.     Leipzig,  1884. 
Frohlich,  A.,  Tumor  der  Hypophyse  ohne  Akromegalie.     Wien.  klin.  Rundschau,  1901, 

Nr.  47,  48. 
Fuchs,  Zur  Friihdiagnose  der  Hypophysentumoren.     Wien.  klin.  Wchenschr.,  1903,  151. 
Gajkiewicz,  cited  by  Sternberg. 
Gallais,  A^.,  Gigantisme  acromegalique  sans  elargissement  de  la  selle  turcique.     Inversin 

sexuelle.     Feminisme  mental.  N.  iconog.  de  la  Salpetriere,  191 2,  124. 
Gaudy,  citation  in  Claude  and  Gougerot. 


624  LITERATURE 

Goetsch,  Cnshing  and  Jacohsohn,  Carbohydrate  tolerance  and  the  posterior  lobe  of  the 

hypophysis  cerebri.     Johns  Hopkins  Hosp.  Bull.,  22,  Baltimore,  June,  191 1. 
Goetzl  and  Erdheim,  Zur  Kasuistik  der  trophischen  Storungen  bei  Hirntumoren.     Ztschr. 

f.  Heilk,  1905. 
Goldstein,  Die  Meningitis  serosa  unter  dem  Bild  hypophysarer  Erkrankung.     Arch.  f. 

Psychiat.,  47,  129,  1910. 
Growe,  dishing,  and  Homans,  Experimental  hypophysectomj'.     Johns  Hopkins  Hosp. 

Bull.,  Baltimore,  May,  1910. 
Haherfeld,  W.,  Die  Rachendachhypophyse.     Beitr.  z.  path.  Anat.  u.  Physiol.,  46,  133, 

1909. 
Hagenhach,  Osteogenesis  imperfecta  tarda.     Frankf.  Ztschr.  f.  Path.,  6,  398. 
Hahl,  C,  Die  Verwendbarkeit  des  Pituitrins  in  der  Geburtshilfe.     Arb.  a.  d.  geburtsh.- 

gynaekol.  Univ.-Klin.  Helsingfors,  191 2,  Verlag  Bergmann. 
Halliburton,  W.  D.,  Candler,  J.  P.,  and  Sikes,  J.  P.     The  human  pituitary  body.     J. 

Physiol.,  38,  1909,  and  Proc.  Physiol.  Soc.  Lond.,  1908-9,  p.  xxxvii. 
Hamburger,  W.  W.,  Action  of  extracts  of  the  anterior  lobe  of  the  pituitary  gland  upon 

the  blood-pressure.     Am.  J.  Physiol.,  26,  178,  1910. 
Hanau,  A.,  Verhandl.  des  X.  internat.  Kongr.  Berlin,  2,  128. 
Hansemann,  Uber  Akromegalie.     Berl.  klin.  Wchenschr.,  1897,  417. 
Hirsch,  O.,  Uber  Mcthoden  der  operativen  Behandlung  von  Hypophysistumoren  auf 

endonasalem  Wege.     Arch.  f.  Laryngol.,  24,  1910.     Also:  Die  operative  Behand- 
lung von  Hypophysentumoren.     Arch.  f.  Laryngol  u.  Rhinol.,  26,  191 2. 
Hochenegg,  Zur  Therapie  von  Hypophysistumoren.     37  Kongr.  d.  Gesellsch.  f.-  Chir., 

1908,  80.     Wien.  khn.  Wchenschr.,  1908,  891.     Ztschr.  f.  Chir.,  Nr.  100,  317. 
Hofbauer,  Hypophysenextrakt  als  Wehenmittel.     Ztschr.  f.  Gynak.,  1910,  137. 
Hofstdtter,  Pituitrin  als  Blasentonicum.     Wien.  klin.  Wchenschr.,  191 1,  1702. 
Howell,  W.  H.,  The  physiological  effects  of  extracts  of  the  hypophysis  cerebri,  etc.     J. 

exper.  M.,  3,  1898. 
Hueter,  C.,  Hypophysistubcrkulose  bei  einer  Zwergin.     Arch.  f.  path.  Anat.  [etc.],  Berl., 

182,  1905. 
Humphrey,  A  case  of  acromegaly  with  hypertrophical  heart.     Brit.  Med.  J.,  8,  Oct.,  1910. 
Hutchinson,  Woods,  A  case  of  acromegaly  in  a  giantess.     Am.  J.  M.  Sc,  1895,  II,  p. 

190. 
Hw/iVze/,  L'acromegalie  chez  I'enfant.     Clinique.     15  Fevr.,  1910,  Nr.  8,  113. 
Josefsohn,  Studier  ofver  Akromegalie  och  hypophysistumorer.     Neurol.  Centralbl.,  1904, 

727. 
Kepinow,   Uber   Synergismus   von   Hypophysisextrakt   und   Adrenalin.     Arch.   f.   exp. 

Path,  und  Pharmakol.,  67,  247,  191 2. 
Klebs,  Allg.  Path.  2,  Jena,  559,  1897. 
Kocher,  T.,  Ein  Fall  von  Hypophysistumor  mit  operativer  Heilung.     Ztschr.  f.  Chir., 

100,  13,  1909. 
Kollarits,  Hypophysentumor  ohne  Akromegalie.     Deutsche  Ztschr.  f.  Nervenh.,  28,  88, 

1905. 
Kon,  Jutaka,  Hypophyscnstudicn.     Beitr.  z.  path.  Anat.  u.  Physiol.,  44,  233,  1908. 
Konig,  Fr.,   Beschreibung  eines   kindlichen  Beckens   und   kindlicher    Geschlechtsteile. 

Inaug.-Diss.  Marburg,  1855. 
Kilmell,  R.,  Zur  Kenntnis   der  Geschwulste  der  Hypophyscngegend.     Miinchen   med. 

Wchenschr.,  191 1,  1293. 
Launois  and  Cleret,  Le  syndrome  hypophysaire  adiposo-genital.     Gaz.  d.  Hop.,   1910, 

Nr.  5  and  7. 
Launois  and  Roy,  Etudes  biologiques  sur  les  geants.     Paris,  1909,  Masson. 


HYPOPHYSIS  625 

■ Glycosurie  et  hypophyse.     Arch.  gen.  de  med.,  5  Mai,  1903. 

Lecene,  M.  P.,  Intervention  chirurgicale  sur  I'Hypophyse.     Presse  med.,  1909,  Nr.  85. 

Lemann  and  van  Wart,  A  case  of  infantilism  with  absence  of  thyreoid  and  tumor  of  pit- 
uitary.    Arch.  Int.  Med.,  May,  5,  519,  1910. 

Levi,  E.,  Contribution  a  I'etude  de  I'infantilisme  du  type  Lorain.  X.  Iconogr.  de  la 
Salpetriere,  21,  297  et  421,  1908. 

—  Rivist.  crit.  di  clin.  med.,  10,  1909. 

Levi  and  Rothschild,  Contribution  and  I'opotherapie  hypophysaire.  Soc  de  neurol.  7 
Fevr.,  1907. 

Loeh,  Beitrage  zur  Lehre  vom  Diabetes  mellitus.     Centralbl.  f.  innere  Med.,  1898,  893. 

Lorand,  Pathogenic  du  diabete  dans  I'acromegalie.     Compt.  rend.  soc.  de  biol.,  Nr.  56, 

554-  _ 

Madelung.  Uber  Verletzungen  der  Hypophysis.     Centralbl.  f.  klin.  Chir.,  1904,  1067. 

Magnus-Levy,  Der  Einfluss  von  Krankheiten  auf  den  Energiehaushalt  im  Ruhezustand. 
Ztschr.  f.  klin.  Med.,  60,  1906. 

Magmis  and  Schdjev,  The  actions  of  pituitary  extract  upon  the  kidney.  J.  Physiol., 
27,  1901,  1902. 

Marafion,  G.,  Lesiones  della  Hypofisis  en  un  caso  de  obesidad  a  hipoplasia  genital.  Bol. 
Soc.  espan.  de  Biol.,  191 1,  Nr.  6. 

Marburg,  Die  Adipositas  cerebralis,  etc.     Deutsche  Ztschr.  f.  Nervenh.,  36,  114,  1904. 

Marek,  cited  by  /.  Novak. 

Marinesco  and  Goldstein,  Deux  cas  d'hydrocephaUe  avec  adipos.  generalisee.  N.  iconogr. 
de  la  Salpetriere,  etc.,  22,  1909. 

Marie,  Pierre,  Sur  deux  cas,  d'acromegalie,  etc.     Rev.  d.  med.,  6,  297,  1886  andL'acrome- 
galie.     N.  iconogr.  de  la  Salpetriere  i,  173,  229,  1888  und  2,  45,  96,  139,  188,  224, 
327,  1889  und  Sur  deux  types  de  deformation  des  mains  de  I'acromeg.     Arch,  de 
.   med.  exper.  et  anat.  path,  [etc.],  1891,  539. 

Marie  and  Marinesco,  Sur  I'anat.  path,  de  I'acromegalie.  Arch.  d.  med.  exper.  et  d'anat. 
path,  [etc.],  1891. 

Massalongo,  R.,  Hyperfunktion  der  Hypophyse,  Riesenwuchs  und  Akromegalie.  Cen- 
tralbl. f.  Nervenh.  u.  Psychiat.,  1895,  281. 

Mayer,  E.,  Uber  Beziehungen  zwischen  Keimdriise  und  Hypophyse.  Arch.  f.  Gyuosk., 
90,  600,  1910. 

Mendel,  reference  in  Deutsche  med.  Wchenschr.,  1906,  1975. 

Meyer,  E.,  Uber  Diabetes  insipidus,  etc.     Deutsches  Arch.  f.  klin.  INIed.,  83,  i. 

Messedaglia,  Studio  suUa  akromegalia.     Padova,  1908. 

Mihalkovics,  Arch.  f.  mikr.  Anat.  u.  EmbryoL,  11,  1875. 

Miller  and  Dean  Lewis,  The  frequency  of  experimental  glycosuria  following  injections  of 
extracts  of  the  hypophysis.     Arch.  Int.  I\Ied.,  May,  1912,  601. 

Mixter  and  Quacqenboss,  Tumor  of  the  hypophysis  with  infantilism.  J.  Surg.,  52, 
July  15,  1910. 

V.  Moraczewski,  Stoffwechsel  bei  Akromegalie,  etc.     Ztschr.  f.  klin.  I\Ied.,  43,  336,  1901. 

Mosse,  G.,  Deformations  acromegaloides.     Soc.  de  Neurol.,  ]Mai,  191 1,  646. 

Moskowicz,  Wien.  klin.  Wchenschr.,  1909,  474. 

Mailer,  E.,  Uber  die  Beeinflussung  der  ^Menstruation  durch  zerebrale  Herderkrankungen. 
Neurol.  Centralbl.,  1905,  79c. 

Naunyn,  Der  Diabetes  meUitus.     Holder,  Wien,  1896. 

Nazari,  Contributo  alio  studio  anatomic-patologico  delle  ciste  dell'  ipofisi  cerebrale 
e  deir  infantilismo.     Policlino,  1906,  445. 

Neil,   tjber  einen  durch  Pituitrin  giinstig  beinflussten  Fall  von  Osteomalazie.     Cen- 
tralbl. f.  Gynak.,  1911,  12. 
40 


626  LITERATURE 

Nenrath,  R.,  Uber  Fettkinder,  etc.     Wien.  klin.  Wchenschr.,  2,  191 1. 

v.  Noorden,  Die  Zuckerkrankheit.     V.  Aufl.  Hirschwald,  Berlin,  1910. 

—  Die  Fettsucht.  II.  Aufl.  Holder,  Wien,  191c. 

Novak,  J.,  Die  Bedeutung  des  weiblichen  Genitales  fiir  den  Gesamtorganismus.     Xoth- 

nagel  Suppl.-Bd.,  1912. 
Olliver  and  Schdfer,  On  the  physiol.  action  of  extracts  of  pituitary  body.     J.  Physiol.,  18, 

277,  1895. 
Oppenheivi,  Diskussion  zum  Vortrag  von  Cassierer  in  Berl.   Gesellsch.   f.   Xeurol.   u. 

Psychiat.,  13,  Nov.,  1899.     Arch.  f.  Psychiat.,  34,  303,  1901. 
Ott  and  Scctt,  The  action  of  infundibulin  on  the  mammary  secretion.     Proc.  soc.  exper. 

Biol,  and  Med.,  8,  48,  191 1. 
Pal,  J.,  Diskussion  in  der  k.  k.  Gesellsch.  d.  Aerzte  Wien.     Sitz.  vom  9,  Juni,  Wien., 

klin.  Wchenschr.,  191 2,  Nr.  24,  938. 
— tjber  die  Gefasswirkung  des  Hypophysenextraktes.     Wien.  med.  Wchenschr.,  1909,  3. 
Paltauf,   A.,   Der  Zwergwuchs  in  gerichtlicher  und  anatomischer  Beiziehung.     Wien, 

1891. 
Paltauf,  R.,  Discussion  on  Asc/mer's  Lecture  before  the  Wien.  Gesellsch.  der  Aerzte,  Dec, 

1909. 
Paulesco,  L'hypophyse  du  cerveau.     Paris,  1908.     Vigot  freres. 
Pechkrantz,  Zur  Kasuistik  der  Hypophysentumoren.     Neurol.    Centralbl.,    1899,  Heft 

5  u.  6. 
Pel,  Acromegalie  partielle  avec  infantilisme.     N.  icongr.  de  la  Salpetriere,  19,  76,  1906. 
Pineles,  F.,  Die  Beziehungen  der  Akromegalie  zum  JNIyxodem  und  anderen  Blutdrii- 

senerkrankungen.     Volkmann's  klin.  Beitr.  N.  F.,  1899,  Nr.  422. 
Pirie,  A  case  of  acromegaly.     Lancet,  5,  Oct.,  1901,  904. 
Poniick,  Myxodem  und  Hypophyse.     Ztschr.  f.  klin.  Med.,  1899,  38,  i. 
Rath,  Beitrag  zur  Symptomenlehre  der  Geschvviilste  der  Hypophysis  cerebri.     Arch.  f. 

Ophth.,  34,  81. 
Rennie,  G.  E.,  Endothehoma  of  the  pituitary  gland  with  infantilisme.     Brit.  M.  J.,  June, 

1912,  150. 
Rose,  Ref.  am.  39,  Kongr.  d.  deutsch.     Gesellch.  f.  Chir.,   1910. 
Rosenhaupt,  Beitr.  zur  Klinik  der  Tumoren,  etc.     Berl.  klin.  Wchenschr.,  1903. 
Rotky,  Klinische  und  radiologische  Beobachtungen  bei  eineni  Fall  von  Akromegalie. 

Fortschr.  a.  d.  Geb.  d.  Rontgenstrahlen,  323,   191c. 
Rumpel,  Fall  von  myxodemartiger  Erkrankung  bei  Hodenatrophie.     Neurol.  Centralbl., 

1896,  428. 
Sabrazes  and  Bonnes,  Examins  du  sang  dans  I'acromegalic.     Conipt.  rend.  soc.  de  biol., 

57.  1905- 
Salbey,  cited  by  Sternberg. 
V.  Salle,  Uber  einem  Fall  von  angeborener  abnormer  Grosse  der  Extremitaten  mit  einem 

an  Akromegalie  erinnernden  Symptomenkomplex.     Jahrb.  f.  Kinderh.,  75,  540, 

1912. 
Salomon,  H.,  Gaswechsel  bei  iNIorbus  Basedowii  und  Akromegalie.     Berl.  klin.  Wchen- 
schr., 1904,  Nr.  24. 
Schdfer,  E.  A.,  Die  Funktionen  des  Gehirnanhanges.     Bern.  M.  Drechsler,  191 1. 
Schdfer  and  Mackenzie,  The  action  of  animal  extracts  on  milk  secretion.     Proc.  Roy. 

Soc.  Lond.,  24,  16,  1911. 
Schlesinger,  W.,  Uber  die  Beziehung   der  Akromegalie  zum  Diabetes  mellitus.     Wien. 

klin.  Rundschau,  1908,  Nr.  15. 
Schloffer,  Erfolgreiche  Operation  eines  Hypophysentumors  auf  nasalem  Wege.       Wien. 

klin.  Wchenschr.,  1907,  621  u.  1075. 


HYPOPHYSIS  627 

Schonemann,  Hypophyse  und  Thyreoidea.     Arch.  f.  path.  Anat.   [etc.],  Berl.,   129,  310, 

1892. 
Schiiller,  Die  Schadelbasis  im  Rontgenbild.     Fortschr.  a.  d.  Gebiet  d.   Rontgenstrahlen 

Erganz.-Bd.,  11. 
SchuUze,  F.,  and  Fischer,  B.,  Zur  Lehre  von  der  Akromegalie  und  Osteoarthropathie  hyper- 

trophiante.     Mitt.  a.  d.  Grenzgeb.,  d.  Med.  u.  Chir.,  24,  607,  191 2. 
SchuUze,  W.,  Fall  von  Akromegalie.     Deutsche  med.  Wchenschr.,  1904. 
Schuster,  Psychische  Storungen  bei  Hirntumoren,  1902. 

Schwoner,  tjber  hereditare  Akromegalie.     Ztschr.  klin.  Med.  Suppl.-Heft,  32. 
Sokoloff,  Ein  Fall  von  Gumma  der  Hypophysis  cerebri.     Arch.  f.  path.  Anat.  [etc.],  Berl., 

143,  333,  1896. 
Sprinzels,  ProtokoU  d.  k.  k.  Gesellsch.  d.  Aerzte  in  Wien,  7,  Juni.     Wien.  klin.  Wchenschr., 

1912,  Nr.  24. 
Sternberg,  Die  Akromegalie.     Nothnagel's  Handb.  VII,  1897. 
Strauss,  Diabetes  insipidus  und  Entwickelungshemmung,  etc.     Folia  urologica  6,  389, 

1912. 
Strilmpell,   Ein   Beitrag  zur  Pathologic  und  pathologischen  Anatomic  der  Hypophyse. 

Deutsche  Ztschr.  f.  Nervenh.,  11,  51,  1897. 
Stumme,  Akromegalie  und  Hypophyse.     Arch.  f.  klin.  Chir.,  87,  1908. 
Souza  Leithe,  De  I'acromegalie.     Paris,  1890. 
Talquist,  cited  by  E.  Meyer. 
Tamburini,  Beitrag  zur  Pathogenese  der  Akromegalie.     Centralbl.  f.  Nervenheilk.  u. 

Psychiat.,  894,  612. 
Uthof,  Wachstumsanomalien  bei  der  temporalen  Hemianopsie  bzw.  den  Hypophysen- 

affektionen.     Deutsch.  med.  Wchenschr.,  1907,  1563. 
Verstraeten,  L'acromegalie.     Rev.  de  med.,  1889,  377  u.  493. 
Widal,  Roy,  Sind  Froin,  Un  cas  d'acromegalie.     Rev.  de  med.,  4,  1906,  313. 
Zak,  E.,  tJber  Hypophysentumoren.     Wien.  klin.  Rundschau.,  1904,  165. 
Zollner,  Tumor  der  Schadelbasis,  ausgehend  von  der  Hypophyse.     i\rch.  f.  Psychiat., 

44,  1908. 


CHAPTER  Vn 

EPIPHYSIS 

Askanazy,  cited  by  Pappenheimer. 

Bailey  and  Jellijfe,  S.  E.,  Tumors  of  the  pineal  body.     Arch.  Int.  I\Ied.,  8,  851,  1911. 

Biach,  P.,  and  Hulks,  E.,  tjber  die  Beziehungen  der  Zirbeldriise  (Glandula  pinealis) 

zum  Genitale.     Wien.  klin.  Wchenschr.,  191 2,  373. 
Coats,  J.,  An  adenoid  sarcoma  with  cartilage  originating  in  the  pineal  gland.     Tr.  Path. 

Soc.  Lend.,  38,  44,  1887. 
Daly,  A  case  of  tumor  of  the  pineal  gland.     Brain,  10,  234,  18S7. 
Exner  and  Boese,  tJber  experimentelle  Exstirpation  der  Glandula  pinealis.     Deutsche. 

Ztschr.  f.  Chir.,  107,  182,  igio. 
Falckso)!,  R.,  Ein  Chondrocystosarkom  im  dritten  Ventrikel.     Arch.  f.  path.  Anat.  [etc.], 

Berl.,  75,  550,  1879. 
Fod,  C,  Hypertrophic  des  Testicules  et  de  la  crete  apres  I'exstirpation  de  la  pineale  chez  le 

coq.     Arch.  ital.  de  biolog.,  57,  233,  191 2. 
V.  Frankl-Hochwart ,  Zur  Diagnose  der  Zirbeldriisentumoren.     Deutsche  Ztschr.  f.  Xer- 

venh.,  37,  1 909. 
Hart,  Ein  Fall  von  Angiosarkoma  der  Glandula  pinealis.     Berl.  klin.  Wchenschr.,  1909, 

2298. 
Heubner,  Tumor  der  Glandula  pinealis.     Deutsche  med.  Wchenschr.,   1898,  Vereins- 

Beil.,  29. 
Ktiy,  Ein  Fall  von  isoliertem  Tumor  der  Zirbeldruse.     Neurol.  Centralbl.,  8,  281,  1889. 
Konig,  tJber  ein  Pseudosarkom  der  Zirbeldruse.     Inaug.-Diss.,  Miinchen,  1894. 
Marburg,  0.,  Die  Adipositas  cerebralis,  etc.     Deutsche  med.  Wchenschr.,  1908,  2009. 

Deutsche  Ztschr.  f.  Xervenh.,  36,  1909,  u.  Wien.  med.  Wchenschr.,  1907,  2512. 
— Die  Epiphyse,  Ergebn.  d.  Xeurol.     Springer,  191 2. 
Mailer,  citation  in  Marburg. 
Neumann,  M.,  Zur  Kenntnis  der  Zirbeldriisengeschwiilstc.     Monatschr.  f.  Psychiat.  u. 

Neurol.,  9,  337,  1901. 
Nothnagel,  Geschwiilste  der  Vierhiigel.     Wien.  med.  Bl.,  1888,  162. 
Oestreich-Slavyk,  Riesenwuchs  und  Zirbeldriisengeschwiilste.     Arch.  f.  path.  Anat.  [etc.], 

Berl.,  157,  475,  1899;  see  also  Heubner,  Tumor  der  Glandula  pinealis.     Deutsche 

med.  Wchenschr.,  1898,  Vereins-Beil.,  29. 
Ogle,  C,  Sarcoma  of  pineal  body.     Tr.  Path.  Soc.  Lond.,  i,  4,  1899. 
Pappenheimer,  Uber  Geschwiilste  des  Corpus  pineale.     Arch.  f.  Path.  Anat.  [etc.],  Berl., 

200,  122,  1910. 
Raymond  and  Claude,  Les  tumeurs  de  la  glande  pineale  chez  I'enfant.     Bull.  Acad,  de 

med.  15  Mars,  1910. 
Weigert,  ZurLehre  von  den  Tumoren  der  Hirnanhange,  Teratom  der  Zirbeldriise.     Arch. 

f.  path.  Anat.  [etc.],  Berl.,  65,  212,  1875. 


628 


CHAPTER  VIII 

SUPRARENALS 

Ahderhalden,  Ztschr.  f.  physiol.  Chem.,  59,  61,  u.  62,  1909. 

Adams,  A  case  of  precocious  development  associated  with  a  tumor  of  the  left  suprarenal 

body.     Tr.  path.  Soc.  Lond.,  56,  1905. 
Addison,  On  the  effects  of  disease  of  the  suprarenal  bodies.     London,  1855. 
Aichel,  O.,  Zur  Kenntnis  der  Nebennieren.     Aliinch.  med.  Wchenschr.,  1900  and  Anat. 

Anz.,  17,  30,  1900. 
Alberti,  Kasuistik  zur  Hypertrichosis   universalis.     Beitr.  z.  Geburtsh.  u.  Gynaek.,  9, 

339,  1905. 
Aldrich,  A  preliminary  report  on  the  active  principle  of  the  suprarenal  gland.     Am.  J. 

Physiol.,  5,  457,  1901. 
Apert,  Dystrophies  en  relation  avec  des  lesions  des  capsules  surrenales  et  progeria.     Bull. 

Soc.  de  pediat.,  Paris,  Dec,  1910,  501. 
— ^La  portion  corticale  de  la  capsule  surrenale,  ses  relations  physiol.  et  path,  avec  le 

cerveau  et  les  glandes  genitales.     Presse  med.,  28  Oct.,  191 1,  865. 
Arnaud,  Les  hemorrhagies  des  capsules  surrenales.     Arch.  gen.  de  med.,  77,  i,  1900,  5. 
Auhertin  and  Amhard,  Lesions  des  capsules  surrenales  dans  les  nephrites  avec  hyperten-. 

sion.     Bull,  et  mem.  soc.  med.  d  hop.  de  Par.  seance  du  19  Fevr.,  1904;  Semaine 

med.,  24,  63,  1904. 
Bayliss,  W.  M.,  and  Starling,  E.  H.,  Die   chemische  Koordination  der  Funktionen  des 

Korpers.  Ergebn.  d.  Physiol.  {Asher-Spiro),  5,  1906. 
Beaujard,  E.,  Les  lesions  surrenales  dans  les  nephrites.     Semaine  med.,  1907. 
Bernstein  andFalta,  tjber  die  Einwirkung  von  Adrenalin,  Pituitrin,  etc.,  auf  den  respira- 

torischen  Stoffwechsel.     29.  Kongr.  innere.  Med.,  191 2. 
Bernstein,   S.,   Uber   den   Blutzuckergehalt   bei   Addisonscher   Krankheit.     Berl.    klin, 

Wchenschr.,  Nr.  40,  1911. 
Bertelli,  Falta,  and  Schweeger,  tJber  die  Wechselwirkung  der  Driisen  mit  innerer  Sekretion 

III.     Ztschr.  f.  klin.  Med.,  Nr.  71. 
Biedl,  Beitrage  zur  Physiologic  der  Nebenniere.     Arch.  f.  d.  ges.  Physiol.,  67,  1897. 
— Innere  Sekretion.     Vorlesungen,  1902.     Wien,  1903.     Wien.  Klin.,  Nr.  29,  1903. 
— Innere  Sekretion.     Urban  u.  Schwarzenberg,  19 10. 
Biedl  and  Braiin,  Zur  Pathogenese  der  experimentellen  Arteriosklerose.     Wien.  klin. 

Wchenschr.,  1909,  p.  709. 
Biedl  and  Wiesel,  Uber  die  funktionelle  Bedeutung  der  Nebenorgane  des  Sympathikus 

{Zuckerandl)  und  der  chromafiinen  Zellgruppen.     Arch.  f.  d.  ges.  Physiol.,  91, 

1903. 
Bierry  and  MaUoizel,  Hj'poglycemie  apres  decapsulation.     Compt.  rend.  soc.  de  bioL,  65, 

232,  1908. 
Bittorf,  Die  Pathologie  der  Nebennieren  und  des  JSIorb.  Addisoni.     Jena,  1908. 
Blum,  Uber  Nebennierendiabetes.     Deutsches  Arch.  f.  klin.  Med.,  71,  1901  and  x\rch.  f. 

d.  ges  Physiol.,  90,  1902. 
Bflinet,  Troubles  nerveux  et  tremblements  observes  chez  un  addisonien  a  la  suite  de  trop 

frequentes  injections  de  capsules  surrenales  de  veau.  Compt.  rend.  soc.  de  bioL, 

51,  891,  1899. 
— De  I'addisonisme.     Arch.  gen.  de  med.,  13  Sept.,  1904. 

629 


630  LITERATURE 

— ^La  mort  dans  la  maladie  bronzee  de  I'addison.     Arch.  gen.  de  med.,  1903,  321. 
Bortz,  Nebennieren  und  Geschlechtscharaktere..  Arch.  f.  Gynaek.,  88,  444. 
Bournevillc  et  Bonnaire,  Sclerose  tubereuse.     Progres  med.,  1881,  667  et  1007. 
Boviii,  Les  tumeurs  hypernephorides  primitives  des  organs  genitaux  feminins.     Nord. 

med.  Arch.  p.  chirurg.,  41,  4,  1909. 
Bramwell,  Anemia  and  some  of  the  diseases  of  blood-forming  organs  and  ductless  glands. 

Edinburgh,  1899. 
Brauii,    Uber    Adrenalinarteriosklerose.     Wien    klin.    Wchenschr.,    1905,  u.    Sitzungsb. 

Akad.  Gesellsch.,  Wien,  1907,  Nr.  116  u.  Med.  Klin.,  1908,  p.  9. 
Brodie  and  Dixon,  Contribution  to  the  physiology  of  the  lungs.     J.  Physiol.,  30,  476,  1904. 
Brodnitz,  Die  Apoplexie  der  Nebennieren.     Miinchen.  med.  Wchenschr.,  1910,  1591. 
Broking,  E.  und  Trendelenburg,  P.,  Adrenalinnachweis  und  Adrenalingehalt  des  mensch- 

lichen  Blutes.     Deutsches  Arch.  f.  klin.  Med.,  103,  168,  191 1. 
Brown-Seqiiard.  Influence  heureux  de  la  transfusion  du  sang  normal  apres  I'exstirpation 

des  capsules  surrenales  chex  le  cobbaye.     Compt.  rend.  soc.  de  biol.,  1893,  448. 
Bulloch,  ]]'.,  and  Scqueira,  G.  H.,  On  the  relation  of  the  suprarenal  capsules  to  the  sexual 

organs.     Tr.  Path.  Soc.  Lond.,  56,  1905. 
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Trendelenburg,  P.,  Bestimmungen  des  Adrenalingehaltes  im  normalen  Blut,  etc.     Arch.  f. 

exper.  Path.  u.  Pharmak.,  63,  161,  1910. 
Ulrich,  Anatomische  Untersuchungen  iiber  ganz  und  partiell  verlagerte  und  akzessorische 

Nebennieren,  etc.     Inaug.-Diss.,  Zurich,  1895. 
Vaquez,  Semaine  med.,  24,  45,  1901,  ibidem,  25,  369,  1905. 
Variot  and  Pironneau,  Nanisme  avec  dystrophie  osseuse  et  cutanee  speciales,  etc.     Bull. 

Soc.  de  pediat.  de  Par.,  June,  1910,  307  et  Clinique  infantile,  8,  705,  1910. 
Vollhracht,  cited  by  v.  Neusser,  and  Wiesel. 
Vonwiller,  Grawitzsche  Nebennierengeschwulst  des  Ovariums.     Beitr.  z.  path  Anat.  u. 

Physiol.,  50,  161,  191 1. 
Watermann  and  Smit,  Nebenniere  and  Sympathikus.     Arch.  f.  d.  ges.  Physiol.,  124,  198, 

1908. 
Weichselbaum,  Beitrage  zur  Geschwulstlehre.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  75,  554, 

1881. 
Westphal,  Fr.,  Die  klinische  Diagnose  der  Grawitztumoren.     Inaug.-Diss.  ]\Iiinchen,  1910. 
Wiesel,  J.,  Uber  die  akzessorischen  Nebennieren  am  Nebenhoden  des  Menschen,  etc. 

Sitzungsbr.  d.  k.  Akad.  d.  Wissensch.  Math.-naturw.  CI.  Wien.,  108,  1898. 
— Mitth.  d.  Gesellsch.  f.  innere  Med.  u.  Kinderh.     Wien.,  1904,  Nr.  3,  144. 
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1903. 
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Anat.  [etc.],  Berl.,  180,  553,  1905. 
— ^Zur  Pathologie  des  chromafi&nen  Systems.     Arch.  fiir.  path.  Anat.  [etc.],  Berl.,  176, 1904. 
— Hemicephalie.     Mitt.  d.  Gesellsch.  f.  innere  Med.     Wien.,  1907,  144. 
Winkler,  Die  Gewachse  der  Nebenniere.     Fischer,  Jena,  1909. 
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Int.  Med.,  June,  1909. 
Wooley,  Adrenal  tumors.     Am.  J.  JMed.  Soc,  1903,  33. 
Zanfrognini,  Eine  neue  kolorimetrische  ^Methode  zur  Adrenalinbestimmung.     Deutsche. 

med.  Wchenschr.,  1909. 
Zander,  tjber  funktionelle  und  kinetische  Beziehungen  der  Nebennieren  zu  anderen 

Organen,  speziell  zum  Grosshirn.     Beitr.  z.  Path.  Anat.  u.  Physiol.,  7,  439,  1890. 
Ziegler,  K.,  Experimentelle  und  klinische  Untersuchungen  iiber  die  Histogenese  der  myel. 

Leukamie,  Jena,  1906. 
Zehbe,  Untersuchungen  iiber  Nierengeschwiilste.     Arch.  f.  path  Anat.  [etc.],  Berl.,  201, 

150. 
Zuckerkandl,  Die  Nebenorgane  des  Sympathikus  im  Retroperitonealraum  des  ]\Ienschen. 

Verhandl.  d.  anat.  Gesellsch.     15.  Versamml.  in  Bonn.  1910,  96. 
Zultzer,  G.,  Zur  Frage  des  Nebennierendiabetes.     Berl.  klin.  Wchenschr.,  1901,  28. 


CHAPTER  IX 

STATUS  LYMPHATICUS  AND  STATUS  HYPOPLASTICUS 

Bartel,  J.,  Uber  die  hypoplastische  Konstitution,  etc.  Wien.  klin.  Wchenschr.,  1907, 
Nr.  38  u.  1908,  Nr.  22. 

BertelU,  Falta,  and  Schweeger,  Uber  die  Wechselwirkung  der  Driisen  mit  innerer  Sekretion. 
III.  Uber  Chemotaxis.     Ztschr.  f.  klin.  Med.,  71. 

Borchardt,  Uber  das  Blutbild  bei  Erkrankungen  der  Driisen  mit  innerer  Sekretion,  etc. 
Deutsches  Arch.  f.  klin.  Med.,  191 2. 

Eppinger  and  Hess,  Die  Vagotonic.  Sammlung  klin.  Abhandlungen  von  v.  Noorden, 
1910,  Heft.  9  u.  10. 

Falta,  W.,  Die  Erkrankungen  der  Driisen  mit  innerer  Sekretion.  Mohr-Staehelinsches 
Handbuch  der  inneren  Medizin,  4,  191 2. 

Hedinger,  Uber  Beziehungen  zwischen  Status  lymphaticus  und  ^Morbus  Addisoni.  Deut- 
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Hermann  and  Kyrle.  Verhandl.  d.  phys.  u.  morph.  Gesellsch.  Wien.,  5,  4,  1909. 

Kolisko,  Uber  plotzlichen  Tod  aus  natiirlichen  Ursachen.  Handb.  d.  arztlichen  Sach- 
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Kimdrat,  H.,  Uber  Vegetationsstorungen.     Wien.  klin.  Wchenschr.,  1893,  Xr.  28. 

Miinzer,  Zur  Lehre  von  den  vaskularen  Hj-potonien.  Wien.  klin.  Wchenschr.,  1910. 
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V.  Neusser,  Ausgewahlte  Kapitel  der  klinischen  Symptomatologie  und  Diagnostik. 
Braumiiller,  191 1,  4.  Heft. 

Paltauf,  A.,  Uber  die  Beziehung  des  Thymus  zum  plotzlichen  Tod.  Wien.  klin.  Wchen- 
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V.  Sury,  Uber  die  fraglichen  Beziehungen  der  sog.  ]Mors  thy  mica  zu  den  plotzlichen 
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Wiesel,  see  chapter  on  suprarenals. 

Wiesner,  Verhandlungen  d.  morph.  u.  physiol.  Gesellsch.  Wien.,  4  ]\Iai,  1909. 


636 


CHAPTER  X 

SEXUAL  GLANDS 

Achard  and  Demanche,  Un  cas  d'atrophie  testiculaire.     Soc.  hop.  med.  de  Paris,  21  Dec, 

1906. 
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ibidem,  1683. 
Apert,  E.,  Obesite,  etat  eunuchoide.,  etc.     Bull.  soc.  pediat.,  Paris,  3,  108,  1901. 
Bahonneix  and  Paisseau,  see  chapter  on  hypophysis. 
Becker,  tjber  das  Knochensystem  eines  Kastraten.     Arch.  f.  Anat.  u.  Physiol.  Anat. 

Abt.,  1899. 
Belfield,  A  case  of  retrograde  puberty  impotence  and  diabetes  insipidus  relieved  by 

suprarenal  cortex.     J.  Am.  M.  Ass.,  55,  215,  July  10,  1910. 
Bellinzona  and  Tritondani,  Ref.  Jahresb.  Ophthalmol.,  1904,  406. 
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Biedl,  Innere  Sekretion.     Ueban  and  Schwarzenberg,  1910. 
Biedl  and  Konigstein,  Untersuchungen  iiber  das  Brustdriisenhormon  in  der  Graviditat. 

'  Ztschr.  f.  exp.  Path.,  8,  358,  1910. 
Bihler,  tJber  das  Verhalten  des  Blutdruckes  bei  Chlorotischen.     Arch.  f.  klin.  Med.,  52, 

281,  1894. 
Birch-Hirschfeld,  Kongr.  f.  innere  Med.,  1892,  28. 
Blumenthal,   Ergebnis   der   Blutuntersuchung  in   der   Geburtschilfe   und   Gynakologie. 

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Bondi,  S.,  Osteomalacic  mit  Struma  und  latenter  Tetanic.     Sitzungsbr.  d.  Gesellsch. 

f.,  innere.  Med.  in  Wien.,  1908,  und  Osteomalacie  beim  Manne,  ibid.,  1910. 
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und  Osteomalacie.     Zentralbl.  f.  Gynak.,  907,  Nr.  3  u.  6. 
Breuer,  R.,  and  v.  Seiller,  R.,  Uber  den  Einfluss  der  Kastration  auf  den  Blutbefund 

weiblicher  Tiere.     Arch.  f.  exper.  Path.  u.  Pharmakol.,  50,  1903. 
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Brown-Sequard,  Expose  des  effets  produits  chez  I'homme  par  les  injections  sous-cutanees. 

Paris,  Masson,  1890.     Arch,  de  physiol.  norm.,  1889,  1890,  1891. 
Bucura,  tJber  die  Bedeutung  der  Eierstocke.  Volkmann's  Vortr.  Neue  Folge  513/514. 
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Capellani,  Ann.  di  ostetr.  et  Ginecol.  2,  Nr.  8. 
Charcot,  Semaine  med.,  Mars,  1891. 
Charrin,  Cited  by  v.  Noorden  and  v.  Jagic. 
Chatin,  Du  chloro-brightisme.  Paris,  1894.     Bailliere  et  fils. 

Chrobak,  tJber  Einverleibung  von  Eierstockgeweben.     Centralbl.  f.  Gynak.,  20,  1S96. 

637 


638  LITERATURE 

Claude  and  Gougcvot,  Insuffisance  pluriglandulaire  endocrinienne.     J.  Physiol,  et  path. 

gen.,  1908,  469  et  505. 
Coffin  and  Lerchoullet,  Atrophic  testiculaire  consecutive  a  une  orchite  surlienne.     Gaz. 

hebd.  de  med.,  1877. 
Comte,  Contribution  a  I'etude  de  I'hypophyse  humaine,  etc.     These  de  Lausanne,  1898. 

Beitr.  z.  path.  Anat.  u.  Physiol.,  23,  1898. 
Cordier  and  Francillon,  Un  cas  d'infantilisme  de  type  reversif  avec  syndromes  pluriglandu- 

laires,  Lyon  med.,  i  Janv.,  1911. 
Cordier  and  Rebattu,  L'infantilisme  regressif  ou  tardif  n.  iconogr.  de  la.  Salpetriere,  191 1, 

405- 
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Physiologic  der  IMilchsekretion,  ibidem,  1521. 
Cristojoletti,  Zur  Pathogenese  der  Osteomalazie.     Gynak.  Rundschau,  5,  191 1. 
Dalc/ic,  Dystrophic  orchidienne.  Bull,  ct  mem.  med.  hop.  de  Par.,  7  Juin,  1901,  2^  Mai, 

1902. 
Davis,  cited  by  ScliUclitcr.     Wien.  klin.  Wchenschr.,  1889,  979. 
Dclbct,  cited  by  Hal  ban. 

Ddderlein,  tjber  Rontgentherapie.     Miinchen.  med.  Wochenschr.,  17,  929,  191 1. 
Dnbnikojf,  Klinischc  Untcrsuchung  iiber  Eiscnwirkung  und  larvicrte  Chlorose.     Disserta- 
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Physiol.,  Vol.  41,  Oct.  1906,  p.  30-54. 
Dnprc,  These  de  Paris,  1904/05. 

Duval,  R.,  Dc  la  secretion  de  la  mammaire  nonpuerperalc.     These  dc  Paris,  1881. 
Engldnder,  B.,  Adrenalin  bei  Knochcnerwcichung.     Centralbl.  f.  Gynak.,  1909,  Nr.  13. 
Eppinger,  Sella  turcica  bei  Hypoplasie  der  Genitalien.     Ges.  f.  inn.  Med.  Wien.  Sitz., 

27  Jan.,  1910. 
Erdheim,  Uber  Epithelkorperchenbcfunde  bei  Osteomalazie.     Stizungsb.  d.  k.  Akad.  d. 

Wisscnsch.  Wien.,  n6,  311.     1907,  Abt.,  3. 
Erdheim  and  Stumme,  Schwangerschaftsverandcrung  der  Hypophyse.     ^liinchen.  med. 

Wchenschr.,  1908,  1202  u.  Beitr.  z.  path.  Anat.  Physiol.,  46,  1909.- 
Etienne,  Jeandelize  and  Richon,  INIalformations  organiques  multiples  chez  un  castrat 

naturel.     Compt.  rend.  soc.  de.  bid.,  62,  1907. 
Falk  and  Hesky,  Uber  Ammoniak-Amminosauren-  und  Peptidstickstoff  im  Harn  Gravider. 

Ztschr.  f.  klin.  Med.,  71,  261,  1910. 
Falta,  W.,  Spiiteunuchoidismus,  etc.     Bcrl.  klin.  Wchenschr.,  No.  30  u.  31,  1912  und  Die 

Krankheiten  der  Drusen  mit  innerer  Sckretion.     Mohr-Stachelinsches  Handb.  d. 

inneren  Med.,  IV.,  191. 
Falta  and  Freund,  Uber  die  Behandlung  innerer  Krankheiten  mit  Radiumemanation. 

IMiinchen.  med.  Wchenschr.,  191 2,  Nr.  14. 
Fehling,  Verhandl.  d.  deutsch.  Gesellsch.  f.  Gynak.  Halle,  1888.     Freiburg,  1889,  interner 

Kongr.,  1890. 
— Die  Form  des  Beckens  beim  Fotus  und  Neugeborenen.     Arch.  f.  Gynaek.,  10. 
— tJber  Wcsen  und  Behandlung  der  Osteomalazie.    Arch.  f.  Gynaik.,  28,  1890  u.  29,  1891. 
Ferrari,  Sulla  clorosi  masc.  della  puberta.     Giorn.  intern,  di  sc.  med.,  1908,  263. 
Fichera,  Sur  I'hypertrophie  de  la  glande  pituitaire  consecutive  a  la  castration.     Arch. 

ital.  de  Biol.,  43,  405,  1905. 
Foa,  C,  Su  fattori  chc  determinano  la  funzione  della  ghiandola  mammaria.     Arch,  di 

Fisiol,  5,  1909. 
Foges,  Zur  Hodentransplantation  bei  Hiihnen.     Centralbl.  f.  Physiol.,  1898. 
Formanolli,  Sur  la  chlorose  masc.     Gazz.  med.  ital,  Torino,  1905. 
Frankel,  Berl.  klin.  Wchenschr.,  Nr.  2,  191 1. 


SEXUAL    GLANDS  639 

Freund,  H.,  Die  Beziehung  der  weiblichen  Geschlechtsorgane,  etc.     Ergebn.  d.  Path. 

Lubarsch-Ostertag,  3,  1896. 
Gall,  cited  by  Mobius. 
Gaillard,  citation  in  Cordier  et  Rebattii. 
Gallavardin  and  Rehattii,  Lyon,  med.,  30  Janv.,  1910. 

Gaudy,  Soc.  med.  d.  hop.  de  Par.,  7,  Dec,  1906,  1226,  17.     Mai,  1907,  et  Juin,  1911. 
Gauthier,  Ein  Fall  von  Milchsekretion  aus  den  Briisten  an  Stelle  der  Menstruation  bei 

einem  jungen  Madchen.     Reference  in  Centralbl.  f.  Gynak.,  1904,  127. 
Geinitz,  citation  in  Kussmaul. 

Giudiceandrea,  Traitement  de  la  chlorose,  etc.     Semaine  med.,  1901,  Nr.  3. 
Giudiceaiidrea,  Archangeli,  and  Bastianelli,  tjber  die  Veranderungen  der  Schilddriisen  bei 

Chlorosis.     Reference  in  Folia  hsematol.,  2,  581. 
Glavecke,  Korperliche  und  geistige  Veranderungen  im  weiblichen  Korper  nach  kiinstlichem 

Verlust  der  Ovarien  und  des  Uterus.     Arch.  f.  Gynsk.,  35, 
Glynn,  see  suprarenals. 

Godard,  Egypte  et  Palestine.     Paris,  1867.     Citation  in  Pelikan. 
Goodman,  The  cyclical  theory  of  menstruation.     Am.  J.  Obst.,  9,  1878. 
Gougerot,  Brisseaiid,  and  Gy,  Insufifisance  endocrinienne  thyroi'do-testiculaire.     Revue 

neurol.  2,  1908.     N.  iconogr.  de  la  Saltpetriere,  24,  449,  1911. 
Grawitz,  Klinische  Pathologic  des  Blutes.     IV.  Aufl.,  191 1,  Verl.  Thieme,  Leipzig. 
Griffith,  The  condition  of  testes  and  prostate  gland  in  eunuchoid  persons.     J.  Anat.,  28, 

1894. 
Grigoriu,  M.  Christea,  Beitrag  zur  Milchsekretion.     Gyngek.  Rudschau.,  4.  Jahrg.,  Nr.  20, 

740. 
Groag,  P.,  Untersuchungen  iiber  Chlorose.     Miinchen  med.  Wchenschr.,  1910,  Nr.  30. 
Guggenheimer,  tJber  Eunuchoide,  etc.     Deutsches,  Arch.  f.  klin.  Med.,  107,  518,  1912. 
Guiyesse,  see  suprarenals. 
Haberer,  v.,  and  Stoerk,  see  suprarenals. 

Halban,  J.,  Die  Entstehung  der  Geschlechtscharaktere.     Arch.  f.  Gyneek,  70,  205,  1903. 
— tJber  den  Einfluss   des  Ovariums  auf  die  Entwicklung  des   Genitales.     Alonatschr. 

f.  Geburtsh.  u.  Gynaek.,  12,  1900,  498. 
— ProtokoU  d.  Gesellsch.  d.  Aerzte.     Wien.  klin.  Wchenschr.,  21,  1910. 
— Die  innere  Sekretion  von  Ovarium  und  Plazenta  und  ihre  Bedeutung  fiir  die  Funktion 

der  Milchdriise.     Arch.  f.  Gynsek.,  75,  1905. 
— Zur  Lehre  von  der  Menstruation,  etc.     Centralbl.  f.  Gynak.,  35,  46,  1911. 
Haller,  A.  v.,  Elementa  physiologica,  8,  116,  1766. 
Halliday,  Crom,  LTeber  einen  Fall  von  tJberpflanzung  des  Ovariums  mit  nachfolgender 

Schwangerschaft  und  Geburt  eines  lebenden  Kindes.     Frage:  Wer  ist  die  Mutter? 

Edinburgh  obstetr.  soc,  1905/06.     (Ref.  Centralbl.  f.  Gynak.,  1906.) 
Hammond,  Am.  J.  Neurol,  and  Psychiat.,  1882. 
Hanau,  tJber  Knochenveranderungen  in  der  Schwangerschaft.     Fortschr.  d.  Med.,  7, 

1892. 
Eandmann,  Schilddriisenveranderungen  und  Hamoglobingehalt  des  Blutes  bei  Chlorose. 

Miinchen.  med.  Wchenschr.,  191 1,  Nr.  22. 
Hastings,  Gilford,  see  pluriglandular  disease. 

Hayem,  A  propos  du  traitement  de  la  chlorose.     Semaine  med.,  1895,  179. 
— De  la  mort  subite  au  cours  de  la  chlorose.     Semaine  med.,  1896,  116. 
Hegar,   Die   Kastration   der   Frauen.     Volkmann's   Samml.,   Nr.    136-138,    1878.     Der 

Geschlechtstrieb,  Stuttgart,  1894. 
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640  LITERATURE 

■ — Korrelation  der  Keimdriisen  und  Geschlechtsbestimmung.     Ibidem  7,  201,  1903. 

Heidenhain,  Hermann's  Handb.  d.  Physiol.,  5,  1883. 

Heyn,  Pseudohermaphroditismus  masculinis  completus.     Ztschr.  f.  Geburtsh.  u.  Gynaek., 

65,  642,  1910. 
HUdcbrandt,  Zur  Lehre  von  der  Milchbildung.     Beitr.  z.  chem.  Phys.  u.  Path.,  5,  463, 

1904. 
Howitz,  citation  in  Pick. 
Hudoveniig,  Un  cas  de  Gigantisme  precoce.  Etude  complementaire,  1906.     N.  icong.  de  la 

Salpetriere,  3,  1903. 
Hudovernig  and  Popovicz,  Gigantisme  precoce  abec  developpement  precoce  des  organes 

genitaux.     N.  iconog.  de  la  Salpetriere,  3,  1903. 
Huntinel,  Pseudochlorose  der  Sauglinge.     AUg.  Wien.  med.  Ztg.,  1908,  408  u.  418.     Trans- 
lated from  Le  monde  med.,  1908,  Xr.  25. 
Immermann,  Krankheiten  des  Blutes.     v.  Ziemssen's  Handb.  d.  spez.  Path.  u.  Therap., 

13,  Abt.,  II,  275-349,  1879. 
Jacob!,  M.,  The  question  of  rest  for  women  during  menstruation.     The  Boylsten  Prize 

Essay  of  Harvard  Univ.  for  1876,  London,  1897. 
Jacobs,  Eierstocktherapie.     Policlinique,  1896. 
Jentzer  und  Beuttner,  Experimentelle  Untersuchungcn  zur  Frage  der  Kastrationsatrophie. 

Ztschr.  f.  Geburtsh.  u.  Gynaek.,  42,  1900. 
Josef  son  and  Lnndquist,  Abnormes  Langenwachstum,  etc.     Deutsche  Ztschr.  f.  Nervenh., 

39,  1910; 
Kekrer,  F.  A.,  Uber  gewisse  synchrone  Nervenerscheniungen  und  zyklische  Vorgange  in 

den  Genitalien  und  anderen  Organen.     Beitr.  z.  Geburtsh.  u.  Gynaek.  4,  228,  1901. 
Kisch,  tJber  Feminismus  mannlicher  lipomatoser  Individucn.     Wien.  med.  Wchenschr., 

1905,  366. 
Klein,  Ein  Fall  von  Pubertas  praecox.     Deutsche  med.  Wchenschr.,  1899,  47. 
Kleinhans  and  Schenk,  Experimentelles  zur  Frage  nach  der  Funktion  des  Corpus  luteum. 

Ztschr.  f.  Geburtsh.  u.  Gynaek.,  66,  283. 
Krauer,  Die  Ovarientransplantation.     Arch.  f.  Gynaek.,  60,  322,  1900. 
Koppen,  citation  in  Recklinghausen. 
Kolisko,  citation  in  Tandlcr  and  Grosz. 

Kon,  Jutaka,  Hypophysenstudien.     Beitr.  z.  path.  Anat.  u.  Physiol.,  44,  1908. 
KoUmann,  Ueber  innere  Sekretion  und  Autolyse  mit  spcziellcr  Beriicksichtigung  der 

Eiweiss-Autolyse  und  klinische  Fragen  iiber  Basedow,  ]\Iyxodem,  Chlorose,  etc. 

Cor.-Bl.  d.  schweiz.  Aerzte,  1910,  Nr.  34. 
Kraft-Ebing,  Psychosis  menstrualis.     Enke,  Stuttgart,  1902. 
Kussmau^,  tJber  geschlechtliche  Friihreife.     Wiirzb.  med.  Ztschr.,  3,  1862. 
Laache,  Die  Anamie.     Christiania,  1883,  785. 
Landau,  M.,  Zur  Behandlung  der  Beschwerden  der  natiirlichen  und  anticipierten  Klimax 

mit  Eierstocksubstanz.     Berl.  klin.  Wochenschr.,  1896,  557. 
— citation  in  Pick. 

Larrey,  Mem.  de  chir.  mil.  et  camp.,  2,  1812. 
Launois  and  Moulon,  Les  cellules  cyanophiles  de  I'hypophyse  chez  la  femme  encente. 

Compt.  rend.  soc.  de.  biol.  Paris,  1903,  448. 
Launois  and  Roy,  Des  relations  qui  existent  entre  I'etat  des  glades  gcnitales  males  et  le 

developpement  du  squelette.     Arch.  gen.  de  med.,  1903,  186. 
Latzko,  Gesellsch.  d.  Aerzte  Wien.     Ref.  Wien.  klin.  Wchenschr.,  1893,  Xr.  17. 
— Wein.  klin.  Wchenschr.,  1894,  Xr.  28  u.  29,  1907,  Nr.  8. 
Leersum,  van,  Uber  die  Ausscheidung  von  Aminosiiuren  wiihrcnd  der  Schwangerschaft 

und  nach  der  Entbindung.     Biochem.  Ztschr.,  11,  121,  1908. 


SEXUAL   GLANDS  64 1 

Lemos  Magelhaes,  Infantilisme  et  degener.  psych.     N.  iconogr.  de  la  Salpetriere,  19,  50, 

1906. 
Leopold  and  Mironow,  Beitrag  zur  Lehre  von  der  Menstruation  und  Ovulation.     Arch.  f. 

Gynsk.,  45,  506,  1894. 
Lohlein,  Erfahrungen  uber  den  Wert  der  Kastration  bei  Osteomalazie.    Ztschr.  f .  Geburtsh. 

u.  Gynsek.,  29,  1894. 
Lowy  and  Richter,  Zur  Frage  nach  dem  Einfluss  der  Kastration  auf  den  Stoffwechsel. 

Centralbl.  f.  Physiol.,  1902. 
Lordet,  Allongement  des  membres  inf.  chez  un  eunuque.     x\rch.  d'anthrop.  crim.     Lyon., 

Par.,  1896.     Soc.  de  med.  deLyon.,  16  Mars,  1896,  in  Lyon  med. 
Lilthje,  tJber  Kastration  und  ihre  Folgen.     Arch.  f.  exper.  Path.  u.  Pharmak.,  48,  184, 

1902. 
Mainzer,  Die  doppelseitige  Ovariotomie  bei  Schwangeren.     IMiinchen.  med.  Wchenschr., 

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Mandl  and  Burger,  Die  biologische  Bedeutung  der  Eierstocke  nach  Entfernung  der  Gebar- 

mutter.     Leipzig  u.  Wien,  1907. 
Marie,  A.,  Eunuchisme  et  erotisme.     N.  iconogr.  de  la  Saltpetriere,  19,  472,  1906. 
Martin,  Gaz.  hebd.,  1877. 
Matthes,   tJber  die   Einwirkung   des   Oophorins   auf   den   Stoffwechsel.     Monatschr.   f. 

Geburtsh.  u.  Gynaek.,  1903. 
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1895. 
Merletti  and  Angeli,  Die  Nebennierentherapie  der  puerperalen  Osteomalazie.     Klin.- 

therap.,  Wchenschr.,  1907,  Nr.  42. 
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Monari,  La  clorosi.     Modena,  1900. 

Morawitz,  Untersuchungen  iiber  Chlorose.     Miinchen  med.   Wchenschr.,   1910,  Nr.  27. 
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Neubauer  and  Novak,  Zur  Frage  der  x\drenalinamie  und  des  Blutzuckers  in  der  Schwanger- 

schaft.     Deutsche  med.  Wchenschr.,  49,  1911. 
Neugehauer,  Hermaphroditismus  beim  ]Menschen.     Leipzig,  190S. 
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klin.  Wchenschr.,  191 1,  Nr.  12. 
Neumann  and  Vass,  Vhtr  den  Einfluss  der  Ovariumpraparate  auf  den  Stoffwechsel. 

Monatschr.  f.  Geburtsh.  u.  Gynsek.,  15. 
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1909. 
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nagel.     Suppl.-Bd.,  191 2. 
41 


642  LITERATURE 

Novak  and  Jeitcr,   Beitrag  zur  Kenntnis  der  puerperalen  Bradykardie.   Monatschr.  f. 

Geburts.  u.  Gynaek.,  1910. 
Oerum,   Quantitative   Blutuntersuchungen.     Deutsches  Arch.   f.   klin.    Med.,  92,   356, 

1908. 
Ott,    Gesetz    der    Periodizitat    physiologischer    Funktionen    im    weiblichen    Organismus 

Centralbl.  f.  Gynak.,  1890,  Beil.  S.,  31. 
Otten,  M.,  Zur  Klinik  der  Chlorose.     Jahrb.  d.  Ham.  Staatskrankenanst.,  10,  1905. 
Pal,  Uber  das  Vorkommen  mydriatisch  wirkender  Substanzen  im  Harne.     Deutsche  med. 

Wchenschr.,  1907,  1735. 
Pankow,  Die  Ursachen  der  Uterusblutungen.     Miinchen.  med.  Wchenschr..  52,  1909. 
Parhon  and  MihaUesco,  Sur  un  cas  d'infantilisme  dj^sth.  et  dysorch.     J.  de  Neurol.,  14, 

210,  1908. 
Pelikan,  Gerichtlich-medizinische  Untersuchungen  iiber  das  Skopzentum  in  Russland. 

Translated  by  Ivanico,  Giessen,  1876. 
PeUizzi,  G.  B.,  La  sindrome  epifisaria  "macrogenitosomia  precoce,"  Riv.,  ital.  di  neuro- 

pat.  [etc.],  3,  1910. 
Peritz,  tJber  Eunuchoide.     Neurol.  Centralbl.,  1910,  1286. 
Pfister,  Die  Wirkung  der  Kastration.     Arch.  f.  Gynaek.,  56,  583,  1898. 
Pfliiger,  E.,  Uber  die  Bedeutung  und  Ursache  der  Menstruation.     Untersuchungen  aus 

dem  physiol,  Lab.,  Bonn.,  1865. 
Pick,  tJber  Neubildungen  am  Genitale  bie  Zwittern.     Arch.  f.  Gynaek.,  76,  191,  1905. 
Pirsche,  De  I'influence  de  la  castration  sur  le  developpement  du  squelette,  Paris,  1902. 
Pittard,  La  castration  chez  I'homme.     Compt.  rend.  Acad.  d.  sc,  1903. 
Plesch,  Hamodynamische  Studien.     Berlin,  Hirschwald,  1909. 
Ploss,  see  Neurath. 
Pommer,  G.,  Untersuchungen  iiber  Osteomalazie  und  Rachitis,  etc.     F.  C.  W.   Vogel, 

Leipzig,  1885. 
Porges  and  Novak,   Uber  die  Ursache   der  Azetonurie  bie    Schwangeren.     Berl.   klin. 

Wchenschr.,  1911,  Nr.  39. 
Pregl,  Zwei  weitere  ergographische  Versuche  iiber  die  Wirkung  orchitischcn  Extraktes. 

Arch.  f.  d.  ges.  Physiol,  de  med.,  62,  1896. 
Rabuteau,  De  I'influence  de  la  menstruation  sur  la  nutrition.     Gaz.  hebd.,  1870.     Jahresb. 

ii.  d.  Fortschr.  d.  Theirchemie,  i,  291,  1871. 
Ravaiio,  Uber  die  Frage  nach  der  Tatigkeit  des  Eierstocks  in  der  Schwangerschaft. 

Arch.  f.  Gynaek.,  83,  587,  1907. 
Rchaudi,  Atti  soc.  ital.  d'obstetr.  e  gin.,  15.     Cited  by  Uoljbaucr,  Arch.  f.  Gynaek.,  93, 

405- 
Recklinghausen,  v.,  Untersuchungen  iiber  Rachitis  und  Osteomalazie,  Jena,  1910. 
Reckling/iausen,  v.,  Festschrift  f.  Virchow,  1891. 
Regis,  cited  by  Novak. 
Reinl,  Die  Wellenbewegung  der  Lebcnsprozesse  des  Weibes.     Volkmanns  Samml.,  1900, 

243- 
— Untersuchungen  iiber  den  Hamoglobingehalt  des  Blutes  in  den  letzten  Monaten  der 

Graviditat.     Beitr.  z.  Geburtsh.  u.  Gyniik.,  Stutrg.,  Stuttgart. 
Reiiss,  v.,  Sehnervenleiden  infolge  von  Graviditat.     Wien.  klin.  Wchenschr.,  1908,  Nr.  31, 

1116. 
Redlich,  Ein  Fall  von  Gigantismus  inf.     Wien.  klin.  Rundschau,  1896. 
Reinhardt,  Adrenalin  und  Osteomalazie.     Centralbl.  f.  Gyniik.,  1907,  Nr.  52. 
Rethers,  Th.,  Beitrage  zur  Pathologic  der  Chlorose.     Dissertation,  Berlin,  1891,  8. 
Rihhert,  Uber  Veranderungen  transplantierten  Gevvebes  Arch.  f.  Entwickelngsmcchn.  d 

Organ,  6,  131,  1897. 


SEXUAL    GLAXDS  643 

• — Uber  Transplantation  von  Ovarien,  Hoden  und  IMamma.  7,  ibidem,  1898. 

Riedel,    ]Menstruatio  praecox   und  Ovarialsarkom.     Wien.  klin.  Wochenschr.,  1904,  942. 

Rieder,  cited  by  v.  Xoorden  und  v.  Jagic. 

Reidinger,  /.,  Uber  Folgen  des  Verlustes  beider  Hoden  am  Ende  der  Wachstumsperiode. 

Ztschr.  f.  orthop.  Chir.,  25. 
Rieger,  C,  Die  Kastration.     Gitsf.  Fischer,  Jena,  1900. 
Rist,  and  Guillemont,  De  roligosideremie  des  jeunes  enfants  et  de  ses  rapports  avec  la 

chlorose  des  jeunes  filles.     Semaine  med.,  1906,  547. 
Roberts,  citation  in  Bischof,  Beweis  der  von  der  Begattung  unabhangigen  periodischen 

Reifung  und  Loslosung  der  Eier.  etc.     Giessen,  1844,  40. 
— Cited  by  Mohkis. 
Romberg,  Bemerkungen  iiber  Chlorose  und  ihre  Behandlung.     Berl.  klin.  Wchenschr., 

1897,  Nr.  25. 
Sacchi,  E.,  Di  un  case  di  gigantismo  infantile,  etc.     Riv.  sper.  di  freniat.,  21,  1895. 
Sainton,  Paul,  Un  cas  d'eunuchoidisme  familial.     X.  iconog.  de  la.  Salpetriere  15,  1902. 
Sainton  and  Diipre,  Les  characteres  cliniques  de  I'insuffisance  testiculaire.     These  de 

Paris,  1904/05. 
Salen,  E.,  Ein  Fall  von  Hermaphroditismus  verus  unilateralis.     Verhandl.  d.  deutsch. 

path.  Gesellsch.,  1899.  241. 
Salomon  and  Saxl,  Beitrage  zur  Karzinomforschung.  1910,  Heft  2. 
Scanzoni,  Schmidt's  Jahrb.,  39,  1853. 

Schauta.  Die  Pygopagenschwestern  Blazek.     Gynsek.  Rundschau.  1910,  437. 
Schmidt,   B.,   Referat  iiber  Rachitis   und  Osteomalazie.     Verhandl.   d.   deutsch.   path. 

Gesellsch.,  1909,  15-17,  April. 
Seiler,  F.,  Uber  lar\aerte  Chlorose.     Cor.-Bl.  f.  Schweiz.  Aerzte,  1909,  Xr.  17. 
Seitz,  Die  Follikelatresie  -^-ahrend  der  Schwangerschaft,  insbesondere  die  Hj'pertrophie 
und  Hyperplasie  der  Theca-interna-Zellen  und  ihre  Beziehung  zur  Corpusluteum- 
bildung.     Arch.  f.  Gynaek.,  77,  203,  1905. 
Sellheim,  Kastration  und  Knochenwachstum.  Beitr.  z.   Geburtsh.  u.  Gynak.,   Leip.,  2, 

1899. 
— Kastration  und  sekundare   Geschlechtscharaktere.       Beitr.  z.  Geburtsh.   u.   Gynak.. 

Leip.,  5,  409,  1 90 1. 
Siegert,  Die  Atiologie  der  Rachitis  auf  Grund  neuerer  Untersuchungen.     ^Sliinchen.  med. 

Wchenschr..  1905.  622. 
Simon,  Hermaphroditismus  verus.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  172,  1903. 
Simonds,  Uber  die  Einwirkung  von  Rontgenstrahlen  auf  die  Hoden.     Fortschr.  a.  d. 

Gab.  d.  Rontgenstrahlalen,  14,  1909/10. 
Slocum,  citation  in  Halban.     Wien.  klin.  Wchenschr.,  1906.  Xr.  i. 
Smith,  K  discussion  on  the  blood  in  disease.     Tr.  Path.  Soc.  London.  2,  311,  1900. 
Starling  and  Lane  Claypon,  Hormon  der  Brustdriise.     Proc.  Roy.  Soc.  London,  77, 1905. 
— Citation  in  Bayliss  und  Starling,  Ergebn.  d.  Physiol.,  5,  664,  1906. 
Steinach,  Willkiirliche  Umwandlung  von  Saugetiermannchen  in  Tiere  mit  ausgepragtem 
weiblichem  Geschlechtscharakter  und  weiblicher  Psyche,    etc.     Arch.  f.  d.  ges. 
Physiol.,  144,  71,  1 91 2. 
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Stieda,  A.,  Uber  einen  im  jugendlichen  Alter  Kastrierten.     Deutsche  med.  Wchenschr., 

1908,  Xr.  18. 
Stacker,  citation  in  Ploss. 

Stoeltzner,   W.,   Schwere   Sauglingsanamie   durch  primaren  Eisenmangel.     Med.   Klin., 

1909,  Nr.  26. 


644  LITERATURE 

Stone,  R.,  Extraordinary  precocity,  etc.     Am.  J.  of  Aled.,  24,  561,  1852. 

Strada,  Patologica,  i,  17,  igog. 

Swiiiarski-Pfannensiiel,  citation  in  Pick. 

Tandler,  J.,  Untersuchungen  an  Skopzen.     Wien.  klin.  Wchenschr.,  1908,  277. 

^Uber   den   Einfluss   der  innersekretorischen   Anteile   der   Geschlechtsdriisen  auf   die 

aussere  Erscheinung  des  Menschen.     Wien.  klin.  Wchenschr.,  1910,  459. 
Tandler  and  Grosz,  Einfluss  der  Kastration  auf  den  Organismus.     Wien.  klin.  Wchenschr., 

1907,  1596. 
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1909. 
— Die  Skopzen.     Ibidem,  30,  1910. 
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Thibierge  and  Gastincl,  Un  cas  de  gigantisme  infant.     N.  iconog.  de  la  Salpetriere,  22,  442, 

1909. 
Trousseau,  Med.  Klinik,  Hotel  de  Dieu.     Wurzburg,  3,  405,  1868. 
Ulilhojf,  Ein  Beitrag  zu  den  Sehstorungen  bei  Zwergwuchs  und  Riesenwuchs  resp.  Akro- 

megalie.     Berl.  klin.  Wchenschr.,  1897. 
Variot,  Observations  sur  un  cryptorchide.     Gaz.  med.  de  Par.,  1892,  76. 
Variot  and  Besanqon,  P.,  Independance  de  la  spermatogene  et  de  la  secretion  testiculaire. 

Bull.  Soc.  anthrop.,  1892. 
Villemin,  Sur  le  role  du  corps  jaune  ovarien  chez  la  femme  et  la  lapine.     Compt.  rend. 

Soc.  de  bioL,  64,  363,  1908. 

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Virchow,  Ueber  Chlorose  and  die  damit  zusammenhangenden  Anomalien  im  Gefass- 

apparat.     BerHn,  1872. 
Walcher,  Verhandl.  deutsch.  Naturforscher  u.  Aerzte.     Stuttgart,  1906. 
Wallart,   J.,   Untersuchungen   iiber   die   interstitielle   Eierstockdriise   beim    IMenschen. 

Arch.  f.  Gynaek,  81,  271. 

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Geburth.  u.  Gynaek.,  61,  851. 
Weher,  M.,  Uber  einen  Fall  von  Hermaphroditismus  bei  Fringilla  coelebs.     Zool.  Anz., 

13,  508,  1890. 
Wetzler,  citation  in  Ploss.     Das  Weib  in  der  Natur-  und  Volkerkunde.     v.  Bartels  Arch., 

I,  1899,  VI.  Auflage. 
Widal  and  Lutier,  Atrophie  congenitale  complete  des  testicules.     Absence  d'infantilisme 

et  de  feminisme.     Bull,  et  men.  Soc.  med.  d.  hop.  de  Par.,  Mars,  191 2. 
Wolf,  Br.,  Zur  Kenntnis  der  Entwicklungsanomalien  bei  Infantilismus  und  bei  vorzeitiger 

Geschlechtsreife.     Arch.  f.  Gynaek.,  94. 
Zander,  Zur  Lehre  von  der  Atiologie,  Pathogenie  und  Therapie  der  Chlorose.     Arch.  f. 

path.  Anat.  [etc.],  Berl.,  84,  177. 
Zangemeistcr,  Die  Beschaffenheit  des  Blutes  in  der  Schwangerschaft  und  der  Geburt. 

Ztschr.  f.  Geburts.  u.  Gynaek.,  49,  92. 
Ziehen,  Demonstration  in  der  Gesellsch.  der  Charite-Arzte  Berlin.     Berl.  klin.  Wchenschr., 

1906,  1905. 
Zoth,   Zwei   ergographische   \'ersuchsreihen   iiber  die   Wirkung   orchitischen  Extraktes. 

Arch.  f.  d.  ges.  Phj'sioL.  62,  1806. 

—  Neue  Versuche  (Hantelversuche)  iiber  die  Wirkung  orchitischen   Extrakts.     Ibidem, 

69,  1898. 
Zuntz,  L.,  Weitere  Untersuchungen  iiber  den  Einfluss  der  Ovarien  auf  den  respiratorischen 
Stoflfwechsel.     Arch.  f.  Gyna?k.,  96,  188,  191 2. 


CHAPTER  XI 

PLURIGLANDULAR  DISEASES 

A  pert,  see  suprarenals. 

Biedl,  Innere  Sekretion.     Urban  u.  Schwarzenberg,  Wien  u.  Berlin,  1910. 

Bollinger,   tjber  Zwerg-  und  Riesenwuchs.   Samml.  gemeinn.   wiss.   Vortr.    Virchow  u. 

V.  Holzendorf,  Nr.  455,  Berlin,  1895. 
Brissaud  and  Meige,  Journal  de  med.  et  chir.  prat.,  25  Janv.,  1895. 
Buday  and  Jansco,  Ein  Fall  von  pathologischem  Riesenwuchs.     Deutsches.   Arch.  f. 

klin.  Med.,  60. 
Claude,  Acromegalie  sans  Gigantisme.     Encephale,  1907,  295. 
Claude  and  Gougerot,  Sur  I'nsufisance  simultanee  de  plusieurs  glandes  a  secretion  interne 

(Insufifisance  pluriglandulaire) .     Compt.  rend.  soc.  de  bioL,  63,  785,  1907. 
Claude  and  Gougerot,  Les  syndromes  d'insuffisance  pluriglandulaire,  leur  place  en  noso- 

graphie.     Rev.  de  med.,  10  Nov.  et  Nov.,  1908,  861,  950. 
Cordier  and  Rehattu,  Infantilisme  regressif  ou  tardif.     N.  iconog.  de  la  Salpetriere,  24, 405, 

1911. 
Gushing,  The  pituitary  body  and  its  disorders.     J.  B.  Lippincott  Co.,  Philadelphia  and 

London. 
Djemil  Pascha,  Un  cas  de  myxoedeme  operatoire,  etc.     Arch,  internat.  de  chir.,  1903,  81. 
Falk,  Fr.,  Gesellsch.  f.  inn.  Med.  u.  Kinderh.,  i  Juni,  191 1.     Wien.  med.  Wchenschr., 

1911,  1819. 
Falta,  W.,  Spateunuchoidismus  und  multiple  Blutdriisensklerose.     Berl.  klin.  Wchenschr., 

Nr.  30  u.  31,  1912. 
Fischer,  B.,  see  hypophysis. 
Gandy,  M.,  Myxoedeme  acquis  de  I'adulte  avec  regression  sexuelle,  etc.     Soc.  med.  d. 

hop.  de  Par.,  7  Dec,  1906,  19,  1226. 

—  Infantilisme  tardif  de  I'adulte.     Bull.  et.  mem.  Soc.  med.  d.  hop.  de  Par.,  Juin,  1911, 

387  et  Bull,  med.,  Juin,  1911. 
Gougerod  and  Gy,  Insuffisance  pluriglandulaire  interne  thyreotesticule  surrenale.     N. 
iconog.  de  la  Salpetriere,  24,  449,  191 1. 

—  Insuffisance  endocrinienne  thyreoido-testicul.     Rev.  neuroL,  2,  1354,  1908. 
Gouilloud,  Soc.  med.  de  Lyon,  14,  ^lay,  1900,  in  Lyon  med. 

Griinfeld,  Sitzungsb.  Deutsche  med.  Wchenschr.,  5,  45,  1901. 

Hastings,  Gilford,  The  disorders  of  postnatal  growth  and  development.     London,  Adlard 
and  Son,  1911. 

—  See  also  Med.  Chir.     Tr.  80,  1897  and  Practitioner  73,  188,  1904. 

Huchard  eind  Launois,  Gigantisme  acromeg.,  etc.     Bull,  et  mem.  Soc.  med.  d.  hop.  dePar., 

Dec,  1903. 
Hutchinson,  Jonathan,  cited  by  Gilford  Hastings. 
Hutchinson,  Woods,  Acromegaly  and  gigantism.     N.  York  M.  J.,  July  21,   1900  and 

Am.  J.  M.  Sc,  1895,  190. 
Josserand,  A  propos  de  I'infantilisme  reversif.     Lyon  med.,  8  Janv.,  191 1. 
Langer,  C.  v.  Wachstum  des  menschlichen  Skelettes  in  bezug  auf.  den  Riesen.     Denkschr. 

d.  kais.  Akad.  d.  Wissenschr.  Wien.  Math-naturw.  KL,  31,  i,  91,  1872. 
Larrey,  Memoires  de  Chirurgie  militaire  et  campagnes,  2,  62,  191 2. 

645 


646  LITERATURE 

Launois  and  Roy,  Des  relations,  qui  existent  entre  I'etat  des  glands  genitales  et  le  develop- 

pement  devie  du  squelette.     Compt.  rend.  Soc.  de  Biol..  10  Janv..  1903,  22  et  X. 

iconog.  de  la  Salpetriere.,  1902. 
—  Etude  biologique  sur  les  geants,  Paris,  1904. 
Levi,  £.,  and  Frachini,  Contribution  a  la  connaissance  du  Gigantisme.  etc.     X.  iconog.  de 

la  Salpetriere,  22,  449,  1909. 
Lorand,  Das  Altern.     Werner  Klinkhardt,  Leipzig,  1910. 
Manasse.  Sitzungsber.     Berl.  klin.  Wchenschr.,  1890,  Xr.  18,  411. 
Marie,  P.,  see  Launois  et  Roy. 

Massalongo,  Suiracromeglia.     Riforma  med.,  1892,  74. 
Meige,  H.,  Sur  le  Gigantisme.     Arch.  gen.  de  Med.  Oct..  1902,  410. 
Noorden,  v.,  Uber  Chlorose.     ]Med.  Klin.,  1910,  Xr.  i. 
Poncet  and  Leriche.  Tuberculose  inflammatoire  des  glandes  vasculaires  sanguines.     Bull. 

Acad,  de  med.,  27  Juin,  191 1. 
Ponfick,  My.xodem  und  Hypophyse.     Ztschr.  f.  klin.  Med..  38,  i,  1899. 
Ransom,  cited  by  Gilford  Hastings. 
Rumpel,  Fa.\\  von  myxodemartiger  Erkrankung  bei  Hodenatrophie.     Xeurol.  Centralbl., 

15,  428,  1896. 
Sainton  and  Rathery.  Myxoedeme  et  tumeur  de  I'hypophyse.     Contribution  a  I'etude  des 

insuffisances  pluriglandulaires.     Bull,  et  mem.  Soc.  d.  hop.  de.  Par..  8  Mai,  1908, 

647. 
Sternberg,  Beitrage  zur  Kenntnis  der  Akromegalie.     Ztschr.  f.  klin.  Med..  27,  1895. 
Thompson,  Atrophy  of  the  parathyreoid  glands  and  other  glands,  structures  in  primary 

infantile  atrophy.     Am.  J.  M.  Sc.  Oct.,  1907,  562. 
Variot  and  Pironneau,  Xanisme  avec  Dystrophic  osseuse  et  cutanee  speciales;  soupgon 

d'agenesie  des  capsules  surrenales.     Bull.  Soc.  de  pediat.  de  Par..  Juin,  1910,  307 

et  la  clinique  infantile,  8,  705,  1910. 
Wiedenmann.  Uber  partiellen  Riesenwuchs.     Beilr.  z.  klin.  Chir..  8,  625,  1892. 


CHAPTER  XII 

VEGETATIVE  DISTURBANCES,  ETC. 

Agosiini,    Infantilismo    distrofico    et    infantilismo    mixoedematoso,    etc.     Riv.  de  patol. 

nerv.,  1902. 
Anion,  Vier  Vortrage  iiber  Entwicklungsstorung  beim  Kind.     Berlin,  1908  und  Reiner 

Psychoinfantilismus.     Forens.  Psychiatric,  1910,  2. 
A  pert   and   Roiiillard,   Juvenilisme   pur.    Origine   dysthroiden   de   I'infantilisme   et    de 

juvenilisme.     Bull,  et  mem.  Soc.  med.  d.  hop.  de  Par.,  28,  84. 
Aschner,  B.,  tJber  einen  Fall  von  hypoplastischem  Zwergwuchs  mit  Graviditat,  etc., 

Monatschr.  f.  Geburtsh.  u.  Gynaek.,  32,  644,  1910. 
Aunet-Breton,  cited  by  di  Gasper 0. 
Baillarger,  cited  by  di  Gaspero. 
Bartel,  see  suprarenals. 

Bauer,  Infantilisme  et  chetivisme.     Presse  med.,  4  Dec,  1909. 
Bertoletti,  M.,  Contribution  a  I'etude  du  Gigant.  acrom.  inf.  N.  iconog.  de  la  Salpetriere, 

1910,  I. 
Bourneville,    Idiotic    und    Infantihsmus.     Kongr.-Ber.     Briissel.     Ref.     Monatschr.    f. 

Kinderh.,  1903,  326. 
Bourneville  and  Bord.     Gas  d'iodiotie  mongoliennc.     Rev.  d'hyg.  et  de  med.  inf.,  5,  221, 

1906. 
Bramwell,  Case  of  infantilism.     Clinical  study,  Edinburgh,  1903,  157. 
Breus  and  Kolisko,  Die  pathologischcn  Beckcnformen  I.     Leipzig  und  Wicn,  Deuticke. 
Brissaud,  Legons  sur  les  malad.  nerv.  (Hop.  St.  Antoine)  Paris,  1899  und  Dc  I'infantilisme 

myx.  N.  iconog.  de  la  Salpetriere,  1897  und  De  I'infantilisme  vrai.  Ibidem,  1907. 
Cestan,  A  propos  d'un  cas  d'achondroplasie.  N.  iconog.  de  la  Salpetriere.,  14,  277,  1901. 
Comby,  Le  mongolisme.     Arch,  de  med.  des  enf.,   1903,   1906  u.   1907.     Bull,  et  mem. 

Soc.  d.  hop.  de  Par.,  1905  u.  1906. 
Dancel,  cited  by  di  Gaspero. 

Decroly,  Policlinique  Bruxelles.     1902,  Nr.  2,  1906,  Nr.  15. 
Diederle,   tJber   endemischen   Kretinismus   und    dessen    Zusammenhang    mit    anderen 

Entwickelungsstorungen.     Jahrb.  f.  Kinderh.,  1906,  465,  576. 
Dolega,  Ein  Fall  von  Kretinismus  beruhend  auf  einer  primaren  Hemmung  des  Knochen- 

wachstums.     Beitr.  z.  path.  Anat.  u.  PhysoL,  9,  488. 
Dufour,  Achondroplasie  partielle,  forme  atypique.     N.  iconog.  de  la  salpetiere,  19,  133, 

1908. 
Dupre  and  P.  Pagniez,  Infantilisme  degen.   (type  Lorain)   complique  de  dysthyreoi'die 

puberale  (type  Brissaud).     N.  iconog.  de  la  Salpetriere,  15,  124,  1902. 
Eichholtz,  Achondroplasia.     Brit.  M.  J.,  i,  1229,  1910. 
Euziere   and   Delmas,   A  propos   d'une   nouvelle   observation  d'achondrodysplasie.     N. 

iconog.  de  la  Salpetriere,  191 1,  380. 
Ferranini,  Uber  den  von  der  Schilddriise  unabhangigen  Infantihsmus.     Arch.  f.  Psychiat., 

38,  1904. 
Franchini,  G.,  et  Zanasi,  M.,  D'achondroplasie  est-elle  hereditaire,  etc.     N.  iconog.  de  la 

Salpetriere,  23,  245,  1910. 
Gaspero,  di,  Der  psychische  Infantihsmus.     Arch.  f.  Psychiat.,  43,  28,  1907. 

647 


648  LITERATURE 

Gilbert  and  Rathery,  Nanisme  mitral.     Presse  med.,  37,  38,  1900. 

Gldssner,  ProtokoU  der  k.  k.  Gesellsch.  d.  Aerzte  in  Wien.     Wien.  klin.  Wchenschr., 

1909,  Nr.  10. 

Gulecke,  Zwergwuchs  infolge  pramaturer  Synostose.     Arch.  f.  klin.  Chir.,  83,  1907. 

Hagenbach,  see  chapter  on  hypophysis. 

Hansemann,  v.,  Echte  Nanosomie,  etc.     Berl.  klin.  Wchenschr.,  1902,  Nr.  52. 

Hegar,  Miinch,  med.  Wchenschr.,   1905,  Nr.   11.     Entwickelungsstorungen.     Deutsche 

med.  Wchenschr.,  1910,  Nr.  40. 
Hertoghe,  De  I'hypothyreoidie  benigne  chronique  ou  myxoedeme  fruste.     N.  iconog.  de  la 

Saltpetriere,  Juli/Aug.,  1899. 
His,  W.,  Zur  Kasuistik  des  Kretinismus.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  22,  104,  1861. 
Eitschmann.     Augenuntersuchungen    bei    Kretinismus    und    Zwergwuchs,    etc.     Wien. 

klin.  Wchenschr.,  27,  1898. 
Holdmoser,  Uber  einen  Fall  von  Zwergwuchs,  verbunden  mit  angcborener  Enge  der  Aorta. 

Wien.  klin.  Wchenschr.,  15,  408,  1899. 
Joachimsthal,  tjber  den  Zwergwuchs,  etc.     Deutsche  med.     Wchenschr.,  1899,  Nr.  17. 
Jofroy,  Paralysie  generale  juvenile,  etc.     Encephale,  1908,  7,  i. 
Kassowitz,  Infantiles  Myxodem,  Mongolismus  und  Mikromelie.     Wien.  med.  Wchenschr., 

1902,  Nr.  22  u.  Forts. 
Katolicky,  ProtokoU  der  Gesellsch.  d.  Aerzte  in  Wien.     Wien.  klin.  Wchenschr.,  1909, 

Nr.  10. 
Kaufmann,  E.,  Untersuchungen  iiber  die  sogennante  fotale  Rachitis.     Berlin,  1892. 
Krauss,  Inaug.-Diss.     Frieburg,  1875. 
Kundrat,  see  status  lymphaticus. 
Lampe,  Inaug.-Diss.     Marburg,  1895. 

Langdon-Down,  Clin.  lect.     A  report  of  the  London  Hosp.,  3,  1866. 
Lange,  Beitr.  zur  pathologischen  Anatomic  des  ]\Iongolismus.     Monatschr.  f.  Kinderh., 

1906,  233. 
Langenbach,  Ein  Fall  von  Chondrodystrophia  foetalis  mit   Asymmetric  des  Schadels. 

Arch.  f.  path.  Anat.  [etc.],  Berl.,  189,  1907. 
Longer.  Ztschr.  d.  Gesellsch.  d.  Arzte  in.  Wien.,  17,  1861. 
Launois,  Essai  biologique  sur  les  nains.     Le  Bull,  med.,  1909,  957. 
Lauze,  De  I'achondroplasie   specialement  etudiee  au   point  de  vue  mentale.     These  de 

Paris,  1910,  335. 
LerebouUet,  Sur  un  cas  de  cirrhose  biliaire  anicteriquc.     Bull.  soc.  de  ped.  de  Paris,  3, 

89,  1901. 

—  Les  cirrhoses  biliaires.     These  de  Paris,  1902,  76. 

Levi,  Ett,  Contribut.  a  la  connaissance  de  la  microsomie,  etc.     N.  iconog.  de  la  Salpetriere, 

1910,  522. 

—  Encore  sur  la  question  des  infantilismes.     N.  iconog.  de  la  Salpetriere,  1910,  20. 
Lorain,  Lettre  preface  a  la  these  de  Faneau  de  la  Cour,  1871. 

Marie,  Pierre,  L'achondroplasie   dans  I'adolescencc  et   I'age   adulte.     Presse   med.,  14 

Juill,  1909. 
Meige,  Remarques  complement aries  sur  les  nains  dans  I'art.     N.  iconog.  de  la  Salpetriere, 

1896  u.  1901,  371. 

—  L'infantilisme.     Gaz.  d.  hop.,  22,  207,  1902. 

Meige,  and  Allard,  Deux  infantiles,  Infantile  myx.  et  infant,  de  Lorain.  N.  iconog.  Sal- 
petriere, 2,  1898. 
Mora,  Fotale  Chondrodystrophie  u.  Thyreodysplasie.     Jahrb.  d.  Kinderh.,  66,  1807. 
Mailer,  H.,  Wiirzb.  med.  Ztschr.,  i,  i860. 


VEGETATIVE   DISTURBANCES,    ETC.  649 

Neumann,  H.,  tJber  den  mongoloiden  Typus  der  Idiotie.     Berl.  klin.  Wchenschr.,  1899, 

210. 
Neurath,  Mongolismus  mit  myxodemahnlichen  Symptomen.     Wien.  med.  Wchenschr., 

1907,  1132. 
Paltauf,  A.,  tJber  den  Zwergwuchs.     Wien,  1891,  Holder. 
Pende,  Begriff  und  Pathogenese  des  Infantilismus.     Deutsches  Arch.  f.  klin.  Med.,  105, 

179,  1910. 
Peretz,  Der  Infantihsmus.     Ergebn.  d.  inn  Med.  u.  Kinderh.,  7,  405,  191 1. 
Poncet  and  Leriche,  Nains  d'aujourdhui  et  nains  d'autrefois.     Ann.  de  med.  et  chir.  inf., 

1903,  Nr.  21. 
Porak,  De  I'achondroplasie.     Cermont,  1890.     N.  Arch,  d'obst.  et  de  gynec,  1890,  19. 

L'obst.,  1905,  249. 
Ranke,  H.  and  Voit,  tJber  den  amerikanischen  Zwerg  Frank  Flynn,  genannt,  General 

Mite,  etc.     Arch.  f.  Anthrop.,  16,  1886. 
Renioul,  Pancreat.  infantilisme.     Brit.  M.  J.,  11,  1694,  1904. 
Richon  and  Jeandelize,  Sur  I'origine  testiculaire  possible  de  certains  cas  d'infantilisme. 

Province  med.,  23  Juin,  1906. 
Saiton,  Les  nains.     Tribune  med.,  8  Mars,  1909. 
Sanctis,  Sante  de,  Gli  infantilismi.     Annali  di  nevrolog.,  26,  1908  and  Riv.  sper.  di  freniat., 

3,  1905- 

Schaafhausen,  Ber.  der  niederrhein.     Gesellsch.  f.  Naturh.,  Bonn.,  25,  1898. 

Schauta,  Die  Beckenanomalien.     Mailer's  Handb.  d.  Geburtsh.,  1888,  308. 

Scholz,  W.,  Kretinismus  und  Mongolismus.     Ergebn.  d.  inn.  Med.  u.  Kinderh.,  3,  505, 

1909. 
Schiiller,  tJber  Infantilismus.     Wien.  med.  Wchenschr.,  1907,  Nr.  13. 
Shuttelworth,  Mentally  deficient  children.     London,  H.  K.  Lewis,  1909,  III.  Edition. 
Siegert,  F.,  Der  Monogolismus.     Ergebn.  d.  innere.  Med.  u.  Kinderh.,  6,  565,  1910. 
—  Der  chondrodystrophische  Zwergwuchs.     Ergebn.  d.  innere  Med.  u.  Kinderh.,  8,  64, 

1912. 
Sommering,  cited  by  Kaufmann. 

Sumita,  Jahrb.  f.  Nervenh.,  73,  1911.     Deutsche  Ztschr.  f.  Chir.,  107,  1911. 
Tandler,  J.,  tJber  Infantihsmus.     Wien.  med.  Presse,  1907,  Nr.  15. 
Taruffi,  cited  by  Levi. 

Vogt,  tJber  den  mongoloiden  Typus  der  Idiotie.     Neurol.  Centralbl.,  1906,  476. 
Weil,  Albert,  Une  famille  d'achondroplasiques.     Bull  et  mem.  Soc.  radiol.  med.  de  Par., 

4,  134,  1912. 
Wolf,  see  eunuchoidism. 

Ziehen,  Ideenassoziationen  des   Kindes.     Samml.  aus  Abhandl.  a.  d.  Gebiet.  d.  Pada- 
gogik.  Psych,  u.  Physiol.,  i,  Heft  6. 


CHAPTER  XIII 

PANCREAS 

Abeimann,  Uber  die  Ausnutzung  der  Nahrungsstoffe  nach  Pankreasexstirpation.     Inaug- 

Diss.  Dorpat,  1890. 
Albu,  Beitrag  zur  Diagnostik  der  inneren  und  chirurgischen  Pankreaserkrankungen. 

Samml.  zwangl.  Abhandl.,  3,  i,  igii. 
Allard,  Die  Acidose  beim  Pankreasdiabetes.     Arch.  f.  exper.  Path.  u.  Pharmakol.,  59, 

388,  1908. 
Asclnicr,  see  chapter  on  hypophysis. 
Ashcr.  Das  Krankheitsbild  des  traumatischen  Diabetes  vorwiegend  vom  forensischen 

Standpunkte.     \'rtljschr.  f.  gerichtl.  ]Med.,  8,  219,  1894. 
Balscr,  Fettnekrose  der  Bauchspeicheldriise.     Arch.  f.  path.  Anat.  [etc.],  Berl.,  40. 
Bencc,  /.,  Untersuchungen  in  einem  Fall  von  Pankreatitis  und  Hepatitis  interstitialis, 

etc.     Wien.  klin,  Wchenschr.,  1907,  Nr.  24. 
Benedict,  Fr.  G.  and  E.  M.  P.  Joslin,  Metabolism  in  Diabetes  mellitus.     Publ.  Xr.  136. 

Carnegie  Institution  of  Washington,  1910. 
Bernard,  Claude,  Vorlesungen  uber  Diabetes,  1878. 
Bernstein  and  Folia,  Uber  die  Einwirkung  von  Adrenalin,   Pituitrinum  infundibulare 

und  Pituitrinum  glandulare  auf  den  respiratorischen  Stoffwechsel,  29.     Kongr.  f. 

innere  Med.,  191 2,  536. 
Biedl,  A.,  Innere  Sekretion.     Urban  und  Schwarzenberg,  igic. 
Biedl,  A.,  and  Th.  Offer,  Uber  Beziehungen  der  Duktuslymphe  zum  Zuckerhaushalt, 

etc.     Wien.  klin.  Wchenschr.,  1907,  1530. 
Du  Bois,  Eugene  F.,  and  Bordeti  S.  Veeder,  The  total  energy  requirement  in  diabetes 

mellitus.     Arch.  Int.  Med.,  5,  37  Jan.,  1910. 
Borchard,  Uber  das  Auftreten  und  die  Ursache  von  Glykosurie,  Albuminurie  und  Cyl- 

indrurie  nach  schweren  Schadelverletzungen.     Monatschr.  f.  Unfallheilk.,  Dec, 

1902;  Wien.  med.  BL,  1903,  27,. 
Boiichardat,  Monographie  sur  le  diabete.     Paris,  1875. 
Burckhardt,   Uber  die  Leistungen  verlagerter  Pankreasstiicke  fiir  die  Ausnutzung  der 

Nahrung  im  Darm.     Arch.  f.  exper.  Path.  u.  Pharmakol.,  58,  251,  1908. 
Cantani,  Diabetes  mellitus.     Translated  by  S.  Hahn,  Berlin,  1880. 
Cdtola,  Un  glioma  dei  plessi  corroidei  de  IV  ventricolo.     Reference  in  Centralbl.   f. 

Neurol.,  1902,  364. 
Cecil,  Russel  L.,  A  study  of  the  pathological  anatomy  of  the  pancreas,  etc.     Proc.  N. 

York  Path.  Soc,  Dec,  1908  and  Jan.,  1909. 
Chauveau  and  Kaufmann,  La  pancreas  et  le  centre  nerveux.     Compt.  rend.  Acad,  de  sc 

1893,  463;  Pathogenie  du  diabete.     Ibid.,  1893,  226. 
Chrelitzer,  Festschrift.     Beitr.  z.  Dermat.  u.  Syph.,  1900. 
Deuchcr,  Stoffwechseluntersuchungen  bei  \'erschluss  des  Ductus  thoracicus.     Cor.-Bl.  f. 

Schweiz.  Aerzte,  28,  327. 
Diamare.  T'.,  Zur  vergleichenden  Physiologie  des  Pankrcas  and  iiber  die  physiologische 

Bedcutung  der  Langerhansschen  Inseln  im  Pankreas.     3.  Mitteilung.     Centralbl. 

f.  Physiol.,  1905,  Nr.  19  und  1908,  Nr.  21. 
Dieckliojf.  Chr.,  Beitrage  zur  pathologischen  Anatomic  des  Pankreas,  etc.,  Inaug.-Diss., 

Rostock,  1894.5 

650 


PANCREAS  651 

Drummond,  David,  Clin,  et  path,  illustrations  of  cerebral  lesions.     Reference  in  Neurol. 

Centralbl.,  1877,  83. 
Diih,  Ein  Beitrag  zur  Lehre  vom  Diabetes  mellitus.     Prag  Vrtljschr.  f.  prakt.  Heilk.,  20, 

I,  1863. 
Dutrait,  Diabetes;  Apoplexie  am  Boden  des  4  Ventrikels.     J.  d.  Bruxelles,  61,  422. 
V.  Ebner,  V .,  Kollikers  Handb.  d.  Gewebelehre,  6  Aufi.,  3,  Leipzig,  1899. 
Ebstein,  Traumatische  Neurose  und  Diabetes.     Arch.  f.  klin.  Med.,  54,  1895. 
Ehrmann,  R.,  Uber  schweren  Diabetes  infolge  syphilitischer  Infektion.     Deutsche  med. 

Wchenschr.,  1908,  Nr.  30. 
Emden  and  Lattes,  tJber  die  Acetessigsaurebildung  in  der  Leber  des  diabetischen  Hundes. 

Beitr.  z.  chem.  Phys.  u.  Path.,  11,  327. 
Eppinger  and  Falta,  see  Falta,  Therapie  des  Diabetes  mellitus.     Ergebn.  d.  inn.  Med. 

u.  Kinderh.,  2,  1908. 
Eppinger,  Falta,  and  Rudinger,  tJber  die  Wechselwirkung  der  Driisen  mit  innerer  Se- 

kretion.     Ztschr.  f.  klin.  Med.,  66  u.  67,  i.  u.  2.  Mitteil. 
Falta,    W.,   tJber   die    Gesetze   der   Zuckerausscheidung   beim   Diabetes   mellitus.     10. 

Mitteil.,   Ztschr.   f.   klin.   Med.,  61,  63,  65  u.  66.     Die  Therapie  des   Diabetes 

mellitus.     Ergebn.  d.  inn.  Med.  u.  Kinderh.,  2. 
• — ■  tJber  die  Bedeutung  der  Blutdriisen  in  der  Pathogenese  des  Diabetes  mellitus.     Prag. 

med.  Wchenschr.,  35,  1910. 
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501. 


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PANCREAS  655 

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1911,  Nr.  5. 


656  LITEIL\TURE 

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—  Untersuchungen  liber  den  Stoffwechsel  bei  Diabetes  mellitus  und  zur  diatetischen  Ther- 

apie  der  Krankheit.     Bibliotheka  medica,  Abt.  D.,  i,  Heft,  1893. 
De  Younghe,  Tumor  der  Medulla  oblongata;  Diabetes  mellitus.     Arch.  f.  Psychiat.,  13, 

658,  1882. 
Ziilzer,  Untersuchungen  uber  den  experimentellen  Diabetes.     24.  Kongr.  f.  innere.  Med., 

1907. 
Ziilzer,  G.  G.,  Dohrn  and  Mayer,  A.,  Neuere  Untersuchungen  iiber  den  experimentellen 

Diabetes.     Deutsche  med.  Wchenschr.,  1908,  1380. 
Zuntz  and  Mayer,  Sur  les  effets  de  la  ligature  des  canaux  pancreatiques  chez  les  chiens. 

Bull.  Soc.  ro)'.  d  med.  pub.  de.  Belg.  Brux.,  19,  409,  1905. 


CHAPTER  XIV 

OBESITY 

Ballet,  G.,  L'adipose  douloureuse  (maladie  de  Dercum).     Presse  med.,  i,  285,  1903. 

V.  Bergmann,  Der  Stoff-  und  Energieumsatz  beim  infantilen  Myxodem  und  bei  Adiposis 

universalis.     Ztschr.  f.  exper.  Path.  u.  Therap.,  5,  640,  1909. 
Bochroch,  A  case  of  adiposis  dolorosa.     Am.  J.  M.  Sc,  124,  569,  1902. 
Burr,  C.  W.,  and  Riesman,  David,  Report  of  a  case  of  tumor  of  the  hypophysis  without 

acromegaly.     J.  Nerv.  and  Ment.  Dis.,  26,  20. 
Cheinisse,  L'identite  de  la  lipomatose  symmetrique  douloureus  avec  la  maladie  de  Der- 
cum.    Semaine  med.,  23,  221,  1903. 
Cegard  and  Roussy,  Deux  cas  d'adipose  douloureus  suite  d'ovariotomie.     Presse  med., 

II,  740,  1903. 
Debove,  Lipomatose  douloureuse.     Gaz.  d.  Hop.,  Nr.  no,  1069,  27  Sept.,  1904. 
Dercum,  A  subcutaneous  connective-tissue  dystrophy  of  the  arms  and  back,  etc.     Univ. 

M.  Mag.,  Dec,  1888,  and  Three  cases  of  a  hitherto  unclassified  affection,  etc. 

Am.  J.  M.  Sc,  114,  521,  1892. 
Dercum  and  McCarthy,  Autopsy  in  a  case  of  adiposis  dolorosa.     Am.  J.  M.  Sc,  124,  994, 

1902. 
Ewald,  Organtherapeutisches.     Therapie  der  Gegenwart,  1899. 
Fulconis,  Maladie  de  Dercum  et  lipomatose  douloureuse  symmetrique.     These  de  Lyon, 

1934. 
Guillain  and  Alquier,  Etude  anatomique  et  pathologique  d'un  cas  de  maladie  de  Dercum. 

Arch,  de  med.  exper.  et  d'anat.  path.,  18,  680,  1906. 
Haskovec,  Lud.,  Adipose  douloureuse  ou  maladie  de  Dercum.     Rev.  neurol.,  Nr.  23,  15 

Dec,  1906. 
Hertoghe,   Hypothyreoidie   benigne   chronique.     N.   inconogr.   de  la   Salpetriere,    1899, 

Nr.  4. 
Jaquet  and  Sevenson,  Zur  Kenntnis  des  Stoffwechsels  fettsiichtiger  Individuen.     Ztschr.  f. 

klin  Med.,  41,  375,  1900. 
Koettnitz,  tjber  symmetrisches  Auftreten  von  Lipomen.     Deutsche  Ztschr.  f.  Chir.,  38, 

75>  1893- 
Launois  and  Bensaude,  De  I'adenolipomatose  symmetrique  a  predominance  cerv.     N. 

inconogr.  de  la  Salpetriere,  13,  41,  184,  243,  1900. 
Loning  and  Fuss,  Schilddriisenveranderungen  bei  Adiposis  dolorosa.     Kongr.  f.  innere. 

Med.,  1906,  222. 
Lorand,  tJber  die  Entstehung  der  Fettsucht,  mit  Riicksicht  auf  Veranderungen  gewisser 

Blutgefassdriisen.     Med.  klin.,  1905,  387. 
Lyon,  J.  P.,  Adiposis  and  lipomatosis  considered  in  reference  to  their  constitutional  rela- 
tions and  symptomatology.     Arch.  Int.  Med.,  6,  28,  1910. 
Magnus-Levy,  Untersuchungen  zur  Schilddriisenfrage.     Ztschr.  f.  klin.  INIed.,  33,  1S97; 

ibid.,  60,  177,  1906. 
Miquel,  De  la  valeur  nosologique  de  la  maladie  de  Dercum.     These  de  Paris,  1904. 
V.  Noorden,  Die  Fettsucht.     Nothnagels  Path.  u.  Therap.  i.  Aufl.,  1900  und  2.  Aufl.,  1910. 

Wien  und  Leipzig,  Holder. 
—  Pathologie  des  Stoffwechsels,  1893,  448. 

42  657 


658  LITERATURE 

V.  Noorden,  Uber  verschiedene  Formen  dcr  Fettsucht.     Med.  Klin.,  Nr.  i. 

—  tjber  Fettsucht.     Med.  Klin.,  Nr.  i. 

—  tJber  Fettsucht.     Intern,  med.  Kongr.,  Budapest,  1909. 

Reach,    Stoffwechselversuch   an   einem   fettleibigen   Knaben.     Festschr.    f.    Salkowski., 

1904,  319,  Berlin. 
Pic  and  Gardere,  Un  cas  d'atrophie  generalisee  de  la  face.     Lyon  med.,  2,  61,  1909. 
Price,  G.  E.,  Adiposis  dolorosa.     .\m.  J.  M.  Sc,  137,  705,  1909. 
Raymond  and  Claude,  see  chapter  on  epiphysis. 
Ruhner,  M.,  Beitrag  zur  Ernahrung  im  Knabenalter  mit  besonderer  Berucksichtigung  der 

Fettsucht,  Berlin,  1902. 
Salomon,  H.,  Uber  Drustkuren,  besonders  bei  der  Fettleibigkeit.     V.  Noorden's  Samml, 

med.  Abhandl.  Berlin,  1905,  Heft  6. 
Schwenckenbecher ,  Uber  die  Adiposis  dolorosa.     Arch.  f.  klin.  Med.,  1904,  324. 
— Uber  die  Ausscheidung  des  Wassers  durch  die  Haut.     Deutsches.  Arch.  f.  klin.  Med.,  79, 

29,  1904. 
Simons,  A.,  EineselteneTrophoneurose  "Lipodystrophia  progressiva."     Ztschr.  f.  Neurol. 

u.  Psychiat.,  5,  191 1. 
Staehelin,  R.,  Der  respiratorische  Stoffwechsel  eines  Fettsiichtigen  im  niichternen  Zustand 

und  nach  Nahrungsaufnahme.     Ztschr.  f.  klin.  Med.,  65,  425,  1908. 
Striibing,  Uber  "Adiposis  dolorosa"  {Derciim)  und  das  "oedeme  blanc  and  bleu."     {Char- 
cot).    Arch.  f.  Dermat.  u.  Syph.,  59,  171,  1902. 
Thiele,  O.,  und  O.  Nehring,  Untersuchungen  des  respiratorischen  Gaswechsels  unter  dem 

Einfluss  von  Thyreoideapraparaten,  etc.     Ztschr.  f.  klin.  Med.,  30,  41,  1896. 
Thimm,  Adiposis  dolorosa  und  schmerzende  Lipome.     Monatschr.  f.  prakt.  Dermat.,  36, 

282,  1903. 
Umber,  Uber  einen  Fall  von  Neurolipomatosis  dolorosa.     Hamburger  arztl.  \'erein,  9. 

Febr.,  1909. 
Vitaut,  Maladie  de  Dcrcum  (Adiposis  dolorosa).     These  de  Lyon,  1901. 
Weiss,  A.,  Adiposis  dolorosa.     Sammelref.  Zntralbl.   f.   Grenzgeb.  d.    ISIed.    u.    Chir, 

7,  Nr.  I,  1904. 
White,  A  case  of  adiposis  dolorosa.     Brit.  M.  J.,  11,  1533,  1899. 


INDEX 


Abderhalden  reaction,  50,  145,  439,  463 
Abscesses  in  the  floor  of  the  ventricle,  554 
Absorptive  disturbances  in    Basedow's  dis- 
ease, 68,  70 

after  extirpation  of  the  pancreas,  510 
"Abwehr"  theories,  50 
Achondroplasia,  see  chondrodystrophy 
Acromegaly,  235 

action  of  adrenalin  in,  265 

blood  picture,  260 

definition,  235 

diabetes  in  263,  276 

differential  diagnosis,  280 

ductless  glandular  system,  259 

early  acromegaly,  277 

eye  changes  in,  266 

genitalia  in,  248 

genital  disturbances  in,  248 

and  gigantism,  454 

hairiness  in,  243 

hpart,  vascular  system,  259 

hypophysial  enlargement,  symptoms  in, 
265 

hypophysis,  267 

mental  disturbances  in,  265 

metabolism,  261 

muscles  in,  236 

myxedema  and,  259 

nerves  and  nervous  system,  263,  266 

occurrence,  235 

osseous  system,  236,  265 

operation  in,  281 

pancreas,  260 

pathogenesis,  269 

pathological  anatomy,  267 

pilocarpine  injection,  264 

polyuria  in,  263,  275 

and  pregnancy,  250 

skin  in,  241 

status  lymphaticus,  260 

suprarenals,  259 

symptomatology,  236 

teeth  in,  237 

thyroid  gland  in,  253 

thymus  gland,  260 

treatment,  281 

vascular  system,  259 


Acromegaliform  syndrome,  276 
Actinomycosis  of  the  thyroid  gland,.  117 
Addison's  disease,  336 

adynamia  in,  336 

blood  picture  in,  337 

course  of,  338 

definition,  336 

differential  diagnosis  of,  347 

gastrointestinal  disturbances  in,  337 

hyperplasia  of  the  thymus  in,  338 

metabolism  of,  337 

occurrence  of,  337 

pathological  anatomy  of,  340 

pathogenesis  of,  346 

pigmentations  in,  337,  346 

prognosis  of,  348 

status  lymphaticus  in,  337 

suprarenal  implantation  in,  348 

symptomatology,  337 

thrombosis  of  the  suprarenals,  348 

treatment  of,  348 
Adenocarcinoma  of  the  hypophysis,  267 

of  the  thyroid  gland,  54 
Adenomata  of  the  hypophysis,  267,  312 

of  the  suprarenals,  356 

of  the  thyroid  gland,  54 
Adiposis  tuberosa  simplex,  587 
Adiposity,  see  obesity. 
Adipositas  dolorosa,  575 

differential  diagnosis,  587 

forms,  582 

mental  symptoms,  583 

and  myxedema,  586 

pathogenesis,  584 

pathological  anatomy,  583 

symptomatology,  581 

treatment,  587 
Adrenalin,  arteriosclerosis  throughinjection 

of,  355 
biological  methods  for  demonstration  of, 

355 
chemical  methods  for  demonstration  of, 

343 

contents   of   the   suprarenal   in   hyper- 
tonia, 354 
in  diabetes,  540 
diuresis  in  diabetes,  540 


659 


66o 


INDEX 


Adrenalin,  general  action,  25.  27 
glycosuria  after  castration,  367 
in  diabetes,  540 

after  extirpation  of  the  pancreas,  506 
in  myxedema,  108 
in  osteomalacia,  435 
in  pregnancy,  377 
in  the  premenstrual  period,  375 
intoxication   in   tumors   of   the   supra- 

renals,  377 
relation  to  iron-free  pigment,  346 
therapy  in  Addison's  disease,  348 
in  Basedow's  disease,  149 
in  esophageal  carcinoma,  350 
in  gastric  ulcer,  349 
in  gynecology,  379 
Adrenalinemia  in  Basedow's  disease,  71 
Adynamia  in  Addison's  disease,  338 
Aged,  ductless  glands,  system  in,  49,  109 
Allen's  treatment  of  diabetes,  569 
Agenitalism,  391 
Alcoholism  in  infantilism,  474 

differential    diagnosis   from    Basedow's 
disease,  98 
Amino-acid  elimination  in  gigantism,  462 

in  tetany,  194 
Ammonia  elimination  in  endemic  cretinism, 
162 
in  gigantism,  462 
in  pregnancy,  377 
in  tetany,  194 
Anencephaly,  suprarenal  aplasia  in,  350 
Angina,  Basedow's  after,  93 
myxedema  after,  118 
thyroiditis  after,  56 
Anoci-association,  50 
Antithyroidin  in  Basedow's  disease,  102 
Aparathyrosis,  177 
Apinealism,  331,  332 
Apituitarism,      14;     see    also     hypophysial 

dystrophy. 
Aplasia  of  the  sexual  glands,  385 
Apoplexia  cerebri  in  diabetes,  553 
Arsenic  in  thyroidin  treatment,  142 
Arteriosclerosis,  in  myxedema,  109 
premature  in  diabetes,  544 
in  suprarenal  hyperplasia,  355 
in  tumors  of  the  sympathetic,  355 
Articular  rheumatism,  myxedema  after,  118 

thyroiditis  after,  56 
Asthenia,  Stiller's,  46 
Asthma  thymicum,  10 
Atheromatosis,  see  arteriosclerosis. 
Athyroidism,  14,  103 
Atropine  in  Basedow's  disease,  81 
general  actions,  25 


Autonomous  ner\-ous  system,  25 
Autolysis,  71 

Balancement  in  pancreatic  tissue,  503 
Basedow's  disease,  57 

blood  picture,  70,  147 

cardiac  vascular  system  in,  58 

in  chlorosis,  429 

complications,  89 

contrasted  with  myxedema,  86 

course  of,  97 

in  diabetes,  565 

diabetes  in,  79 

in  diagnosis,  98 

diarrheas  in,  68 

definition,  57 

dj-sf unction  in,  85,  145 

emaciation  in,  75 

etiology,  93 

eye-symptoms,  61 

fat  stools  in,  68,  70 

formes  frustes,  94,  96,  97 

forms  of,  91 

gastrointestinal  tract,  67 

genitalia,  83 

glycosuria  in,  79 

heat,  regulation  in,  81 

heart  and  vascular  system  in,  58 

iodine  contents  of  the  thyroid  gland,  91 

mental  symptoms  in,  66 

metabolism  in,  75 

muscles  in,  66 

ami  myxedema,  89 

nervous  system  in,  65 

osseous  system  in,  83 

pathogenesis  of,  84 

pathology,  148 

pigmentation  in,  82 

prognosis,  98 

psyche  and  psychoses,  66 

relations  with  epilepsy,  147 

respiratory  organs  in,  64 

scleroderma  and,  83 

skin,  82 

sympathicotonic,  95 

symptomatology,  58 

tachycardia  in,  60 

temperature  in,  82 

thymus  glands  in,  152,  175.  229,  230 

after  thyroiditis,  56 

treatment,  98,  148 

tremor  in,  66 

vagotonic,  95 
Basedowoid,  95 

Bladder   disturbances   in   hypophysial   dys- 
trophy, 294 


INDEX 


66i 


Bladder  disturbances  in  tetany,  192 
Blood  coagulability  after  castration,  397 

distribution  after  injection  of  adrenalin, 

343 
Blood  picture  in  acromegaly,  260 

in  Addison's  disease,  337 

after  injections  of  adrenalin,  343 

in  Basedow's  disease,  70,  172 

after  castration,  431 

in  chlorosis,  429 

in  diabetes,  542 

in  endemic  cretinism  and  goiter,  147, 
165,  172 

in  hypophysial  dystrophy,  298 

in  infantilism,  472 

in  multiple  ductless  glandular  sclero- 
sis, 446 

in  myxedema,  108,  112 

in  osteomalacia,  437 

in  the  premenstrual  period,  375 

in  sporadic  cretinism,  134 

in  status  lymphaticus,  365 

in  tetany,  185 

in  thymus  gland  hyperplasia,  227 

after  extirpation  of  the  thymus  gland, 
224 
-pressure,   after  injection  of  adrenalin, 

344 

in  Addison's  disease,  336 

in  Basedow's  disease,  60 

in  chlorosis,  428 

in  hyperplasia  of  the  chromaffin  tissue, 

353 

in  multiple  ductless  glandular  sclero- 
sis, 446 
in  the  permenstrual  period,  375 
after  use  of  pituitrinum  glandulare, 

273 
of     pituitrinum     infundibulare, 
271 
regulation  of,  by  the  ductless  glands, 

27 
in  status  lymphaticus,  366 
after  sugar  puncture,  516 
after  thyroid  feeding,  60 

in  diabetes,  542 
sugar  after  adrenalin  injection,  343 
after  cervical  cord  transection,  32 
in  diabetes  mellitus,  527 
in  hypertonia,  355 

after  injections  of  pituitrinum  glandu- 
lare, 274 

of  pituitrinum  infundibulare,  272 
after  pancreas  extirpation,  504,  514 

in  birds,  512 
in  phosphorus  posioning,  350 


Blood  sugar  after  peroral  administration  of 
adrenalin,  348 
regulation  of,  through  the  chromaffin 

tissue,  346 
after  suprarenal  extirpation,  342 
in  tetany,  221 
Brain  tumors  and  diabetes,  555 
Brj'son's  sj^mptom  in  Basedow's  disease,  65 

Cachexia  thyreopriva,  104 
Calcium  metabolism  in  endemic  cretinism, 
163 
after  castration,  396 
in  neurasthenia,  38 
in  osteomalacia,  436 
in  tabes,  38 
in  tetanjr,  195 
therapy  in  Basedow's  disease,  102 
in  tetany,  210 
Caloric  production  in  diabetes,  537 

see  metabolism. 
Calzine  in  Basedow's  disease,  102 

in  tetany,  219 
Carbohydrate  metabolism,  16 
in  Basedow's  disease,  78 
in  brain  diseases,  38 
in  chlorosis,  429 
chromafl&n  tissue  and,  355 
in  diabetes  meUitus,  527 
after  extirpation  of  the  pancreas,  503 
after  injection  of  pituitrin,  272,  274 
after  ligation  of  the  pancreatic  duct,  506, 

511 

in  rnyxedema,  113 

regulation  through  the  ductless  glands, 
16,  565,  566 

in  tetany,  193 
Carcinoma  of  the  epiphysis,  330 

of  the  hypophysis,  262 

of  the  pancreas,  524,  525 

of  the  suprarenal  cortex,  356 

of  the  thyroid  gland,  54 

of  the  thymus  gland,  228 
Carpopedal  spasm,  181 
Castration,  blood  picture,  397 

loss  of  pigment,  393,  396 

oophorin  action,  397 

in  osteomalacia,  435 

respiratory  metabolism,  396 

see  also  eunuchs. 
Cataract  formation  in  tetany,  197 
Catatonia,  metabolism,  37 
Chemotactic  actions  of  the  hormones,  27,  28, 

34 
Chlorosis,  42 

cardiovascular  symptoms,  428 


662 


INDEX 


Chlorosis  and  eunuchoidism,  428 

generative  glands  in,  481 

genitalia  in,  430 

infantile,  428 

pathogenesis,  431 

syinptomatology,  428 

tardive,  428 
Chlorotoid,  428 

Cholelithiasis  and  pancreatitis,  520 
Cholin,  general  action,  25 

in  the  suprarenal  cortex,  3,  345 

systeme  cholingene,  345 
Choked  disc  in  acromegaly,  267 

in  epiphysial  tumors,  330 

in  tetany,  183 
Chondrodystrophy,  484 

definition,  485 

differential  diagnosis,  493 

etiology,  493 

familial  occurrence,  491 

forms,  489 

occurrence,  491 

partial,  487 

symptomatology,  485 

unilateral,  488 
Chondroma  of  the  hypophysis,  312 
Chromaffin  tissue  in  chlorosis,  433 

in  diabetes  mellitus,  566 

in  Grawitz  tumors,  357 

in  hypertonia,  353 

in  osteomalacia,  437 

in  phosphorus  poisoning,  350 

physiology  of,  342 

in  status  lymphaticus,  366 

m  sugar  puncture,  316,  317 

in  tetany,  200 

in  thymus-gland  hyperplasia,  227 

tumors  of,  352 
Chvostek's  symptom   in   diabetes   mellitus, 
179 

in  tetany,  178 

in  the  tuberculous,  179 
Cirrhose  bronz^e,  10 
Cirrhosis,  see  sclerosis. 

of  the  liver  in  infantilism,  474 
Climacteric,  384 
Conarium,  see  epiphysis. 
Colloid  in  the  hypophysis,  116 

in  the  thyroid  gland,  55,  156 
Conjunctivitis  in  endemic  cretinism,  159 

in  tetany,  184 
Constitution  and  ductless  glands,  12,  46-49 
Correlation,  see  reciprocal  action. 
Corpus  luteum,  377 

Creatinin  elimination  in  Basedow's  disease, 
81 


Creatinin  elimination,  in  endemic  cretinism, 
162 
in  tetany,  194 
Creatdrrhea,   in    diseases    of   the    pancreas, 

523 
Cretinic   degeneration,   geographical    distri- 
bution of,  155 
Cretinism,  endemic,  154 

blood  picture,  165 

brain,  160 

dentition,  165 

differential  diagnosis,  171 

epiphysial  junctures,  164 

etiology,  171 

genitalia,  163 

growth  disturbances,  164 

habitus,  158 

hearing  disturbances,  161 

hypophysis,  163 

intellectual  disturbances,  162 

metabolism,  162 

mutism  in,  161 

nervous  systems,  160,  162 

parathyroid  glands,  166 

pathogenesis,  169 

pathological  anatomy,  160 

respiratory  metabolism  in,  162 

skeleton,  164 

skin,  158 

speech  development,  162 

symptomatology,  158 

teeth  in,  165 

thyroid  gland,  165 

treatment,  166 
marine,  170 
sporadic,  120 

blood  picture,  134 

definition,  120 

dentition,  133 

differential  diagnosis,  138 

enlargement  of  the  liver,  133 

epiphysial  junctures,  131 

etiology,  138 

genitalia,  133 

growth  disturbances,  130 

hearing  disturbances,  136 

hypophysis,  136 

hypothermia,  136 

metabolism,  135 

nervous  system,  136 

patholpgy,  121,  122 

respiratory  metabolism,  135 

symptomatology,  123 

thymus  gland,  136 

t  refitment,  138 

umbilical  hernia,  133 


INDEX 


663 


Crile,  see  kinetic  theory  and  anoci-associa- 
tion. 

Cryptorchidism,  371 

in  partial  gigantism,  463 

Cyst  goiters,  156 

Cysts  of  the  epiphj-sis,  330 

of  the  hypophysis,  268,  312 

of  the  pancreas,  518 

of  the  suprarenal  cortex,  357 

Cysticerci  of  the  floor  of  the  ventricle,  554 

Definition  of  ductless  glandular  secretion,  4 

of  internal  secretion,  4 
Degeneratio  genito-sclerodermica,  450 
Dentition  in  endemic  cretinism,  165 

in  myxedema,  105 

in  premature  development,  426 

in  sporadic  cretinism,  133 

in  tetany,  197 
Dercum's  disease,  see  also  adiposis  dolorosa, 

575 
question  of  pluriglandular  disturbance, 

43 
Dermatographism  in  diabetes  mellitus,  542 

in  tetany,  183 
Detoxication  theory  of  Basedow's  disease,  84 
Diabetes  insipidus,  idiopathic  in  brain  dis- 
eases, 294 
in  diseases  of  the  hypophysis,  321,  322 
mellitus,  499 

in  acromegaly,  263 
adrenalin  diuresis,  541 

glycosuria,  540 

production,  355 
after  adrenalin  injection,  517 
adrenalinogenic,  562 
alimentary  factor,  527,  528,  562 
in  Basedow's  disease,  79 
blood  picture,  542 
blood  pressure  increase  through  thy- 

roidin  in,  542 
in  brain  tumors,  555 
carbohydrate  metabolism,  527 
in  cerebral  hemorrhage,  553 

lues,  560 

tumors,  555 
clinical  aspect  of,  518 
complications  of,  544 
decipiens,  541 
dermatographism,  542 
diet  in,  567,  569 
differential  diagnosis,  566 
in  diseases  of  the  hypophysis,  565 
diuresis,  541 
in  eunuchoidism,  409 
experimental  nervous,  515 


Diabetes  mellitus,  after  extirpation  of  the 
pancreas,  503,  514 

from  fat,  529 

genuine,  526 

granular  atrophv  of  the  pancreas  in, 
546 

after  head  injury,  556 

hj-pertonic,  29,  38,  543,  569 

hydropic  insular  degeneration,  549 

insular  theory,  547 

ketonuria,  530 

in  m\^edema,  115 

nervous  factor  of  the  glycosuria,  529 

obstipation  in,  541 

pancreas  hormone,  507 

parathyroids  and  extirpation  of  the 
pancreas,  506 

pathological  anatomy  of,  546 

after  pituitrinum  glandulare  injec- 
tion, 517 

premature  arteriosclerosis,  544 

protein  metabolism,  529 

question  of  disturbance  of  glycogene- 
sis,  of  the  disturbance  of  sugar  com- 
bustion, and  of   sugar  production, 

of    the   formation   of    sugar    from 
protein,  528 
quotient  D:  N,  513,  530 
respiratory  metabolism,  531 
salt  metabolism,  530 
Sandmej'er's,  504 
Allen's  treatment  of,  569 
theor_v,  549,  561 
thj^rogenic,  565 
after  trauma,  556 
treatment,  567,  569 
vegetative  nervous  system,  540 
water  econom}',  530 
Diaphragm  spasm  in  tetany,  181 
Diarrheas  in  Basedow's  disease,  67 
Diathesis,  47 

exudative,  367 
hypertonic,  355 
spasmophilic,  213 
Diet  in  diabetes  mellitus,  567,  569 
Diphtheria,  adrenalin  treatment  of,  349 
suprarenals  in,  341 
toxin  suprarenals  in  injection  of,  341 
Diplopia  in  tetanj^,  181 
Dissociation  of  the  hormone  actions,  1 1 
Diuresis  in  diabetes,  541 

in  hypophysial  tumors,  294 
Ductless  glands  in  adipositas  dolorosa,  585, 
586,  588 
autonomy,  33 


664 


INDEX 


Ductless  glands,  degeneration  in  gigantism, 
462 
grouping  of,  22 
in  hypergenitalism,  425 
hypoplasia  of,  449 
influence  of,  on  hairiness,  391 

on  the  sexual  characters,  390 
in  pregnancy,  378 
in  progeria,  452,  453 
regulation  of  the  metabolism,  16 
sugar  metabolism,  565 
glandular  diseases,  etiology  and  patho- 
genesis, 35 
sclerosis,  multiple,  441 
blood  picture,  446 
case  histories,  442 
definition,  442 
differential  diagnosis,  453 
etiology,  448 

late  eunuchoidism  in,  446 
secondary,  452 
symptomatology,  445 
treatment,  453 
Ductus  thyreoglossus,  53 
Dwarfism,  in  cretinism,  130,  164 
hypophysial,  301 
hypoplastic,  474,  477 
Paltauf's  type,  481 
primordial,  480 
rachitic,  484 

in  suprarenal  tuberculosis,  351 
true,  480 
Dysfunction,  10-13 

in  Basedow's  disease,  85 
in  marine  cretinism,  171 
Dysthyrosis,  85 
Dystrophia  adiposo-genitalis,  282 

eunuchoid,  see  eunuchs  and  eunuchoid- 
ism, and  late  eunuchoidism  in  gigan- 
tism in  epiphysial  tumors,  330 
Dystrophy,  hypophysial,  282 
in  acromegaly,  278 
adrenalin  action,  293 
bladder  disturbances,  293 
blood  picture,  298 
definition,  283 
differential  diagnosis,  324 
genitalia,  289 
growth  disturbances,  301 
heat  regulation,  297 
infantilism,  302,  477 
metabolism,  290 
obesity  in,  283 
pathological  anatomy,  311 
pilocarpine  action,  293 
polyuria,  294 


Dystrophy,  psj-che,  311 
skeleton,  306 
symptomatology,  283 
thermoreaction,  298 
tumor  sj'mptoms  in,  311 
vegetative  nervous  system,  293 

Early  acromegaly,  277 
Eclampsia,  205,  207 
Edema  in  Basedow's  disease,  82 
Edeme  neuropathique  Mathieu,  585 

segmentaire  Debove,  585 
Eleodona  moschata,  203 
Electrical    hyperexcitability  in  tetany,  177, 

178' 
Embryology  of  the  ductless  glandular  sys- 
tem, 20 
Enamel,  defects  of  the  enamel  in  tetany,  197 
Encephalomalacia  in  diabetes,  553 
Endothelioma  of  the  dura  mater,  325 

of  the  suprarenal  cortex,  356 
Eosinophiles  in  acromegaly,  260 

after  injection  of  adrenalin,  343 

in  cretinism,  165 

in  ductless  glandular  sclerosis,  446 

in  osteomalacia,  437 

postpartum,  383 

in  status  lymphaticus,  365 
Epilepsy  in  Basedow's  disease,  145 

in  ductless  glandular  sclerosis,  449 

in  tetany,  182,  217,  218 
Epiphysial  junctures  in  Basedow's  disease,  38 

in  chlorosis,  430 

in  chondrodystrophy,  486 

in  cretinism,  131,  164 

in  dwarfism,  480,  482,  483 

in  early  acromegaly,  278 

in  eunuchoidism,  407 

in  eunuchs,  393 

in  hypophysial  dystrophy,  310 

in  late  eunuchoidism,  419 

in  progeria,  452 

in  rachitis,  484 

in  sporadic  cretinism,  131 
Epithelial  bodies,  see  parathyroids. 
Erb's  symptom  in  tetany,  177 
Ergotin  poisoning,  209,  211 
Eunuchoidism,  397 

in  acromegaly,  438 

blood  findings,  410 

case  reports,  377 

definition,  397 

differential  diagnosis,  411 

from  hypophysial  dystrophy,  411 
from  infantilism,  411 

genitalia,  408 


INDEX 


665 


Eunuchoidism,  hair  in,  408 

metabolism,  409 

obesity,  407 

pathogenesis,  410 

prognosis,  412 

skeleton,  405 

suprarenal  hypoplasia,  in,  351 

symptomatology,  405 

treatment,  412 
Eunuchs,  391 

occurrence,  391 

skeleton  in,  393 

skin  in,  393 

symptomatology,  391 
Exophthalmus  in  acromegaly,  255,  311 

in  Basedow's,  62 

Fat  stools  in  Basedow's,  70 

in  pancreatic  diseases,  522,  523 
Ferment  production  in  Basedow's,  68 
Fetalism,  479 

Fibrillary  contractions,  see  muscles. 
Fibroma  of  the  hypophysis,  312 
Freundian  hypothesis,  50,  53,  145 
Function,  pharmaceutical  testing  of,  25 
Fundamental  exchange,  18;  see  respiratory 
metabolism. 

Galactogenous  substances  in  the  hypophysis, 

272 
Galactorrhea  in  acromegaly,  248 
Galactosuria  in  visceral  neuroses,  38 
Gartner's  duct,  370 

Gas  metabolism,  see  respiratory  metabolism. 
Gastric  tetany,  214 

treatment  of,  220 
Gastrointestinal   disturbances   in   Addison's 
disease,  336 
in  Basedow's  disease,  67 
in  chlorosis,  428 
Gelatinous  struma  of  the  thyroid  gland,  55 
Generative  apparatus,  374 
Genitalia  in  acromegaly,  248 

in  Basedow's  disease,  83 

in  chlorosis,  430 

in  chondrodystrophy,  490 

in  endemic  cretinism,  163 

in  eunuchoids,  408 

in  extirpation  of  the  hypophysis,  315, 
316,  317 

in  gigantism,  456,  459 

in  hypophysial  dystrophy,  289^ 

in  infantilism,  472 

in  late  castrates,  394,  395 

in  late  eunuchoidism,  418 

in  marine  cretinism,  170 


Genitalia  in  Mongolism,  496 

in  myxedema,  115 

in  sexual  glandular  tumors,  425,  426 

in  sporadic  cretinism,  133 

in  suprarenal  tumors,  359 

in  thymus  tumors,  228 

under  thyroidin  treatment,  412,  422 

in  tumors  of  the  epiphysis,  331 
Genu  valgum  in  eunuchoidism,  407 
Gigantism,  454 

and  acromegaly,  248,  280,  454 

in  chlorosis,  430 

hypophysis  in,  461 

late  eunuchoidism  in,  459 

partial,  463 

pathology,  460 

transient,  in  suprarenal  cortical  tumors, 
362 

types,  459 
Glioma  of  the  epiphysis,  330 

of  the  suprarenals,  352 

of  the  floor  of  the  ventricle,  555 
Glycogen,  loss  after  suprarenal  extirpation, 
342 

mobilization  through  adrenalin,  343 
Glycosuria  in  acromegaly,  264 

through  adrenalin,  343 

after  castration,  397 

in  cerebral  hemorrhage,  553 
syphilis,  560 
tumors,  555 

in  chlorosis,  429 

in  diabetes  mellitus  (laws),  527 

in  eunuchoidism,  409 

in  extirpation  of  the  hypophysis,  315 

after  head  injury,  556 

in  hypophysial  dystrophy,  291 

after  injection  of  pituitrinum  glandulare, 

275 
of  pituitrinum  infundibulare,  273 
in  myxedema,  115 
nervous,  529 
in  pain,  559 
in  sugar  puncture,  344 
after  trauma,  556 
Goiter,  155 

blood  picture,  172 
heart,  156 

differential  diagnosis  from  Basedow's 
disease,  98 
iodine  treatment,  156 
noxus,  155 
in  tetany,  211 
Goiter,  exophthalmic;  see  Basedow's  disease. 
Gonorrheal    orchitis  in  late   eunuchoidism, 
461 


666 


INDEX 


Grafe's  symptom  in  Basedow's,  63 
Granular  atrophy  of  the  pancreas,  546 
Grawitz  tumors,  356 

Growth,  regulation  of,  on  the  part  of  the 
ductless  glandular  system,  1 1 
disturbance,  1 1 

in  cretins,  130,  164 

in  epiphysial  tumors,  330 

in    eunuchs    and     eunuchoids,    393, 

407 
after  extirpation  of  the  thymus  gland, 

225 
in  hypophysial  dystrophy,  301 
in  idiots  (Mongolian),  496 
influencing  of,  through  thyroidin,  143, 

167 
in  late  eunuchoidism,  419 
in  suprarenal  diseases,  351,  358 
in  tetany,  199 

see  also  osseous  sj'stem  and  epiphysial 
junctures. 

Hair  growth,  see  hairiness. 
Hairiness  in  acromegaly,  243 

in  epiphysial  tumors,  330 

in  eunuchoids,  408 

in  eunuchs,  393 

in  hypergenitalism,  425 

in  infantilism,  473 

in  late  eunuchoidism,  419 

in  pregnancy,  378 

in  suprarenal  tumors,  361 
Hearing  disturbances  in  myxedema,  104 

in  sporadic  cretinism,  136 

thyroidin  treatment  in,  142 
Heart  disturbances  in  chlorosis,  428 

in  tetany,  183,  184 

see  also  vascular  system. 
Heat  regulation,  19,  20 

especially    through     the     chromaffin 
tissue,  343 

in  Basedow's  disease,  81 

in  brain  diseases,  38 

through  the  ductless  glands,  19 

in  hypophysial  dystrophy,  297 

in  myxedema,  115 

in  neuroses,  38 

in  the  premenstrual  period,  375 

in  tetany,  192 
Hematopoietic  apparatus,  33-35 

see  also  blood  picture. 
Hemichromatopsia,  bitemporal,  328 
Hemochromatosis,  449 
Hemorrhages,  in  the  parathyroids,  207,  208, 

213 
Hemosiderosis,  10 


Hermaphroditism,  386,  438 

Historical  dev-elopment  of  ductless  glandular 

diseases,  1-6 
Hoffman's  symptom  in  tetany,  178 
Hormones,  5 

Hydrocephalus  in  aplasia  of  the  suprarenal 
medulla,  340 

in  endemic  cretinism,  160 

in  hj'pophysial  dystrophy,  315 
Hydrochloric    acid    treatment  in  Addison's 

disease,  349 
Hydrotherapy  in  Basedow's,  102 
Hyperacidity  in  Basedow's,  67 

in  chlorosis,  428 

in  tetany,  188 
Hypergenitalism,  424 

in  tumors  of  the  epiphysis,  330 

in  suprarenal  tumors,  358 
Hyperglobulia  through  injection  of  adrenalin, 
108,  343 

in  tetany,  185 
Hyperglycemia,  504 

in  injection  of  adrenalin,  343 

see  also  blood-sugar. 
Hj'^pernephroma,  357 

in  Addison's  diseasCj  340 
Hyperparathyroidesia,  221 
Hyperpinealism,  132,  332 
Hyperpituitarism,  14;   sec  also   acromegaly 

and  early  acromegaly. 
Hyperthermia  after  injection  of  adrenalin, 

343 

in  Basedow's  disease,  81 

in  brain  diseases  and  neuroses,  38 

in  tetan3%  192 
Hyperthymization,  226 
Hyperthj^roidism,  see  Basedow's  disease. 
Hypertonia,  see  blood-pressure. 
Hypertrichosis,  390 

in  suprarenal  tumors,  359,  363 
Hypertrophy,  vicarious,  of  suprarenals,  341 
Hypoparath^'rosis,  177 
Hypophysis,  231 

anatomy,  231 

in  adiposis  dolorosa,  583 

and  diabetes  insipidus,  294,  296 

in  ductless  glandular  sclerosis,  447 

in  endemic  cretinism,  164 

in  gigantism,  454,  459,  462 

effect  on  growth,  15 

in    hypophysial    dystrophy    (see    dys- 
trophy-), 311 

in  marine  cretinism,  171 

in  myxedema,  116 

in  obesity,  574 

pathological  anatomy,  267 


INDEX 


667 


Hypophysis,  physiology   and  pathology,   2, 
270 

in  pregnancy,  379 

relation  to  the  thyroid  gland,  323 

respiratory  metabolism  after  extirpation 
of,  290 

in  sporadic  cretinism,  122,  136 

tablets,  treatment  with,  326 
Hypopinealism,  332 

Hypopituitarism;  see  dystrophy,  hypophysial. 
Hypoplasia  of  the  parathyroid,  213 
Hypothermia  in  brain  diseases,  38 

in  hypophysial  dystrophy,  297 

in  myxedema,  115 

in  sporadic  cretinism,  136 
Hypothyroidism,    14,    104;    see  myxedema 

and  sporadic  cretinism. 
Hypothyrosis,  85 
Hysteria,  37,  50 

differential  diagnosis  from  tetany,  217 

Idiots,  121 

Imidoazolylethylamin,  211 
Implantation  of  the  thyroid  gland,  139 
Indicanuria  in  cerebral  diseases,  38 
Infantilism,  45,  465 

blood  picture  in,  472 

classification,  473 

definition,  468 

differential  diagnosis,  475 
from  eunuchoidism,  476 

etiology,  474 

forms,  473 

genitalia  in,  472 

in  osteomalacia,  437 

pancreaticus,  478 

pathogenesis,  479 

prognosis,  479 

symptomatology,  472 

transitional  forms,  477 

treatment,  479 
Influenza,  thyroiditis  after,  56 
Insufiisance  pluriglandulare,  441 
Insular  apparatus  of  the  pancreas,  502 
Interstitial  glands,  330 

see  also  sexual  glands. 
Intestinal  colics  in  Addison's  disease,  336 

disturbances,    see   gastrointestinal    dis- 
turbances. 
Intoxication  theory,  12 
Iodine  Basedow's  disease,  92 

in  the  pathology  of  the  thyroid  gland,  91 

treatment  in  goiter,  156 
lodism,  92 
lodothyrin,  140 
Iron  therapy  in  chlorosis,  435 


Juvenilism,  479 

Kalzine  in  Basedow's  disease,  102 

in  tetany,  219 
Ketonuria  in  diabetes,  530 

after  extirpation  of  the  pancreas,   505 

in  pregnancy,  378 
Kinetic  theory,  50 

Lachrymation  in  tetany,  184 

Langerhans's   islands   in    diabetes    mellitus, 

546 
Laryngospasm  in  tetany,  181 
Larynx  in  acromegaly,  237 

and  eunuchoids,  407 

in  eunuchs,  393 
Late  castrates,  394 

eunuchoidism,  413 
Lead  poisoning,  differential  diagnosis  from 
Basedow's  disease,  98 

in  tetany  patients,  209 
.  Leucorrhea,  cyclical,  377 
Levulose  in  diabetes,  mellitus,  528 
Levulosuria  in  the  vasomotor  neuroses,  38 
Lipodystrophia  progressiva,  584 
Lipoidemia  in  pregnancy,  377 
Lipomatoses,  585,  587 
Lowi's  reaction,  8,  29,  30,  506 

in  diabetes,  543 
Lymphatism,  365 

in  ductless  glandular  diseases,  366 

in  sporadic  cretinism,  135 
Lues,  see  syphilis. 
Luetin  tablets,  423 

Malaria,  thyroiditis  after,  56 
Malformations  of  the  sexual  glands,  385 
Magnesium   sulphate  treatment  of   tetany, 

222 
Mammary  glands  in  hypergenitalism,  426 

in  pregnancy,  381 
Melancholia,  37 

in  Basedow's,  66 

in  myxedema,  no 
Melanoma  of  the  suprarenals,  356 
Menstruation,  relation  to  ovulation,  376 

precocious,  426 
Metabolism,  in  acromegaly,  261 

Addison's  disease,  337 

in  adipositas  dolorosa,  583 

after  adrenalin  injection,  343 

in  Basedow's  disease,  75 

after  castration,  396 

in  chlorosis,  429,  430 

in  cretinism,  162 

in  diabetes  mellitus,  527 


668 


INDEX 


Metabolism    after    extirpation    of  the   hy- 
pophysis, 316 

gigantism  in  hypophysial  dystrophy,  290 

in  infantilism,  473 

in  myxedema,  112 

in  pregnancy,  373 

regulation  through  the  ductless  glandu- 
lar system,  16-20 

see  also  carbohydrate  metabolism,  pro- 
tein metabolism,  salt  metabolism, 
respiratory  metabolism,  and  purin 
metabolism. 

under  treatment  with  thyroidin,  140 
Methyl  cyanide,  84 
Mikulicz's  syndrome,  43 
Mobius's  symptom  in  Basedow's,  63 
Molimina  menstrualia,  373 
Mongolism,  494 

Mononucleosis,  see  blood  picture. 
Mors  thymica,  226,  230 
Mucin  in  the  tissues  in  myxedema,  105 
Miiller's  duct,  370 

Multiple    ductless   glandular    sclerosis,    see 
ductless  glandular  sclerosis  multiple. 
Muscular  atrophy,  progressive,  471 

system  in  acromegaly,  241 
in  eunuchoids,  408 
in  eunuchs,  393 

mechanical  hyperexcitability,   i,   180 
in  tetany,  180,  184 
Musset's  sign,  59 
Mutism,  161 
Myasthenia,  41 

and  tetany,  221 
Myoma  uteri,  relation  to  goiter,  156 
Myoneural  junction,  344 
Myotonia,  41 

in  tetany,  180,  182,  184,  218 
Myxinfantilism,  see  infantile  myxedema  and 

sporadic  cretinism. 
Myxedema,  104 

in  acromegaly,  241 

in  Basedow's  disease,  89 

blood  picture,  108,  112,  147,  148 

cardiovascular  system  in,  106-108 

contrasted  with  Basedow's  disease,  87 

course,  117 

definition,  104 

and  diabetes,  1 1 5 

differential  diagnosis,  118 

ductless  glandular  sclerosis,  446 

etiology,  117 

formes  frustes,  119 

genitalia,  115 

glycosuria  in,  114,  115 


Myxedema,  hair  in,  105 

hearing  disturbances,  104 

heat  regulation,  115 

hypophysis,  116 

in  hypophysial  dystrophy,  284 

in  infantilism,  476 

mental  symptoms  in  no 

metabolism,  112 

metabolism   under   thyroid    treatment, 

113 

incomplete  forms,  hypothyroidism,  119 

in  Mongolism,  497 

nervous  system,  106,  108,  109,  no,  itr 

occurrence,  104 

osseous  system,  1 1 1 

psyche,  no 

in  scleroderma,  118 

skin,  104,  109,  III 

symptomatology,  104 

after  thyroiditis,  118 

vascular  system,  106,  108 

Nanisme  type  senile,  405 
Narcosis  death  in  thymus  hyperplasia,  226 
Nervous    diseases    and    ductless    glandular 
system,  37 
system,  somatic  and  vegetative  in  Ad- 
dison's disease,  336 
in  acromegaly,  263,  266 
in  adrenalin  injection,  343,  344 
in  Basedow's  disease,  65 
in  the  climacteric,  384 
in  cretinism,  136,  160,  161 
in  diabetes,  540 
in  eunuchoidism,  410 
hypophysial  dystrophy,  293 
in  infantilism,  473 

in  myxedema,  106,  108,  109,  no,  in 
in  neurofibromatosis,  353 
in  osteomalacia,  438 
after  extirpation  of  the  parathyroids 

201,  204 
after  extirpation  of  the  pancreas,  506 
in  rachitis,  484 
relations    to    the   ductless   glandular 

system,  23,  37 
sexual  glands,  384 
after  sugar  puncture,  516 
in  tetany,  177,  184 
after  extirpation  of  the  thymus  gland, 
224-226 
Neurofibroma,  353 
Neuroses,  37,  50 
Nicotine,  25 

in  infantilism,  474 


IXDEX 


669 


Nicotinism,  differential  diagnosis  from  Base- 
dow's disease,  98 

Oats  treatment  in  diabetes,  567,  569 
Obesity,  in  i\ddison's  disease,  337 

in  Basedow's  disease,  75 

in  epiphysial  tumors,  331 

in  eunuchs,  393 

forms  (exgenous,  endogenous),  570 

in  hypophysial  tumors,  283,  317,  574 

in  hydrocephalus,  283 

in  late  castratus,  419 

in  late  eunuchoids,  414,  419 

pancreatogenic,  572 

respiratory  metabolism,  570 

in  suprarenal  cortical  tumors,  359 

thj^rogenic,  573 
Oophorin  tablets,  423 

metabolism  on  the  use  of,  396 
Operation  in  Basedow's,  99,  150,  151 
Opotherapie  associee,  43,  44,  453 
Orchitis,  gonorrheal,  416 

after  mumps,  416 

syphilitic,  416 
Osseous  system  in  acromegaly,  236,  265 

in  Basedow's  disease,  83 

in  chondrodystrophy,  486 

in  cretinism,  130,  164 

in  eunuchoids,  405 

in  etinuchs,  392 

in  idiots,  172 

in  myxedema,  1 1 1 

in  tetany,  196,  199 

see  also  epiphysial  junctures. 
Osteitis,  Paget 's,  281 
Osteoarthropathie  hypertrophiante,  281 
Osteomalacia,  439 

in  tetany,  199 

treatment,  327 
Osteophjrte  formation  in  pregnancy,  379 
Osteoporosis  congenita,  493 
Ovaraden,  423 
Ovarian  tablets,  423 
Ovaries,  see  sexual  glands. 
Ovarin,  423 
Ovulation,  376 

Oxyproteinic  acid  elimination  in  pregnancy, 
378 

Pancreas,  absorption  disturbances,  508,  511 
in  acromegaly,  260,  276 
anatomy,  501 
colics,  521 
embryolog],^,  501 
extirpation,  503 


Pancreas,  hormone  of  Ziilzer,  508 

lithiasis,  521 

ligation  of  excretory  duct  of,  509 

pathological  anatomy,  518 

physiology,  504,  508 

role  of,  in  fattening,  573 

sclerosis,  521 
Pancreatitis,  518 
Paraganglia,  335,  353 
Paragangliomata,  353 
Paralysis  agitans,  41,  221,  463 
Paralysis,  progressive,  38,  42 
Parathyroids,  anatomy,  174 

in  adipositas  dolorosa,  555 

detoxication  theory,  202 

in  endemic  cretinism,  166 

embryology,  175 

function,  201 

importance  for  life,  201 

nerv'ous  system,  203 

in  osteomalacia,  437 

in  pregnancy,  381 

in  thyroaplasia,  122 

see  also  tetany. 
Parathyroanititoxin,  219 
Parathyroid  tablets,  210 
Pedatrophy,  450 
Pellagra  in  infantilism,  474 

pigmentation  in,  348 
Pentosuria  in  neurosis,  38 
Peptid  nitrogen   elimination  in  pregnancy, 
378 

in  tetany,  194 
Peremeschko's  medullary  layer,  233 
Placenta,  internal  secretion  of,  382 
Plasma   contents   of    the  blood    regulation 

through  the  chromaffin  tissue,  27 
Pharmacological  tests  of  function,  25,  52 
Physostigmine,  25 
Pigmentation  in  Addison's  disease,  337,  346 

in  animals  deprived  of  suprarenals,  347 

in  Basedow's  disease,  82,  347 

in  chlorosis,  429 

in  cirrhosis  bronzee,  347 

in  ductless  glandular  sclerosis,  446 

in  Grawitz  tumors,  357 

in  leucemia  of  the  suprarenals,  348 

in  m\Tiedema,  348 

in  osteomalacia,  437 

in  pellagra,  348 

in  pregnancy,  378 

in  suprarenal  cortical  tumors,  357 

in  tetany,  196 

in  the  tuberculous,  347 
Pigment,  loss  of,  after  castration,  396 


670 


INDEX 


Pilocarpine,  action  in  acromegaly,  264 

in  cretinism,  133 

general  action,  25 

in  hypophysial  dystrophy,  293 

in  myxedema,  no 

in  tetany,  184 
Pineal  gland,  see  epiphysis. 
Pituitary  gland;  see  hypophysis. 
Pituitrinum  glandulare,  28,  273,  327 
in  osteomalacia,  436 

therapeutic  use,  327 
thermoreaction,  298 

infundibulare,  28,  271,  272,  327 
in  acromegaly,  264 
in  osteomalacia,  436 
in  sexual  glandular  insufficiency,  422 
therapeutic  use,  326 
Pluriglandular  diseases,  42,  449 
Polyuria  in  bitemporal  hemianopsia,  294 

in  cerebral  syphilis,  294 

in  diabetes,  571 

in  ductless  glandular  sclerosis,  447 

after  extirpation  of  the  pancreas,  505 

in  hypophysial  dystrophy,  294 

in  tumors  of  the  epiphysis,  331 
Postbranchial  bodies,  53,  122 
Pregnancy,  377 

cells,  136,  379 

hypertrophy  of  the  suprarenal  cortex, 
363,  378 

hypophysis  in,  379 

reaction,  383 

parathyroids  in,  381 

placenta,  382 

tetany,  in,  214 

thyroid  gland,  381 
Premature  development,  14 

in  tumors  of  the  epiphysis,  331 
Progeria,  450 
Prostate,  370 

in  eunuchoidism,  408 

in  eunuchs,  392 

in  late  eunuchoidism,  418 

in  new-born  boys,  383 
Protein  metabolism,  16 

in  Basedow's  disease,  77 

in  catatonia,  37 

in  diabetes,  529 

in  myxedema,  112 

in  extirpation  of  the  pancreas,  37 

in  psychoses,  37 

in  tetany,  194 
Protrusio  bulbi  in  Basedow's,  61 
Psammoma  of  the  epiphysis,  330 
Pseudochlorosis,  430 
Pseudoodeme  catatonique  Dide,  585 


Pseudohermaphroditismus,  386,  387 

in  tumors  of  the  suprarenals,  360 
Psyche  in  Basedow's,  66 

in  chondrodystrophy,  493 

in  eunuchoidism,  410 

in  tumors  of  the  epiphysis,  331 

in  hypophysial  dystrophy,  311 

in  infantilism,  473 

influence  of  the  sexual  glands,  384 

in  myxedema,  1 10 

in  sexual  glandular  tumors,  425 
Psychoses,  ductless  glands  in,  38 

in  Basedow's,  66 

in  hypophysial  dj^strophy,  311 

in  myxedema,  no 
Purin  metabolism,  17 

in  acromegaly,  263 

in  brain  diseases,  38 

in  eunuchoidism,  409 

in  hypophysial  dj^strophy,  291 

regulation  through  the  ductless  glands, 

17 

Pylorospasm  in  tetany,  189 

Quinine  in  Basedow's  disease,  81 

in  thyroiditis,  56 
Quotient  (D  :  N)  in  diabetes  mellitis,  537 

after  extirpation  of  the  pancreas,  506 

respiratory,  see  respiratory  quotient. 

Rachitis,  484 

tetany  in,  212 
Radium  treatment  in  eunuchoidism,  413 

in  hypergenitalism,  427 
Rathke's  cysts,  242 
Raynaud's  disease,  38 

Reciprocal  action  of  the  ductless  glands,  6-10 
Reichmann's  disease  in  tetany,  179,  220 
Respiration  calorimeter,  531 
Respiratory  metabolism,  17 

in  acromegaly,  261 

after  adrenalin  injection,  343 

in  Basedow's,  78 

in  cretinism,  135 

in  eunuchoidism,  409 

after  extirpation  of  the  pancreas,  505 

in  obesity,  570,  571 

after  pituitrin  injection,  273 

regulation  by  ductless  glands,  17 

in  tetany,  194 
organs  in  Basedow's  disease,  64 
quotient  after  adrenalin  injection,  343 

in  Basedow's,  76 

in  diabetes,  531 

after   exclusion   of   the   subdiaphrag- 
matic circulation,  514 


INDEX 


671 


Respiratory   quotient    after    extirpation   of 
the  pancreas;  505 

after  injection  of  pituitrin,  273 
Retinitis  in  acromegaly,  266 

in  tetany,  286 
Rodagen,  102 
Rontgen,  examination,  etc.,  see  X-ray. 

Salt  metabolism  in  acromegaly,  262 

after  extirpation  of  the  pancreas,  505 
Sarcoma  of  the  epiphysis,  330 
of  the  hypophysis,  312 
of  the  sexual  glands,  426 
of  the  suprarenal  cortex,  376 
of  the  thymus  gland,  228 
of  the  thyroid  gland,  54 
Schlesinger's  symptom,  180 
Scleroderma,  ductless  glands  in,  39 
in  Addison's  disease,  348 
with  myxedema,  118 
pigmentations,  348 
thyroidin  treatment,  144 
Sclerose  tubereuse  du  cerveau,  356 
Sclerosis,  multiple,  41 
of  the  pancreas,  521 
of  the  parathyroids,  207 
premature,   of  the  cerebral  arteries  in 

tetany,  216 
of  the  thyroid  gland,  56 
Sella  ttorcica  in  acromegaly,  221 
after  castration,  393 
in  eunuchoids,  407 
in  eunuchs,  393 
in  hypophysial  dystrophy,  311 
in  myxedema,  116 
in  sporadic  cretinism,  136 
in  thyroidless  animals,  116 
Senilism,  48 

Sensorium  in  tetany,  183 
Sertoli's  cells,  370 
Sexual  characters  in  chlorosis,  431 
in  eunuchs,  13,  392 
in  premature  development,  425 
relation  to  the  sexual  glands,  388 
in  suprarenal  cortical  tumors,  358 
glands,  369 
see  also  interstitial  glands,  genitals, 

generative  apparatus, 
in  Addison's  disease,  337 
in  adipositas  dolorosa,  584 
anatomy,  370 
aplasia,  385 
in  chlorosis,  430 
in  chondrodystrophy,  490 
in  climacteric,  384 
in  diabetes,  544 


Sexual     characters     in     ductless    glandular 
sclerosis,  446 
in  eunuchoids,  13,  408 
in  gigantism,  459 
in  hermaphroditism,  384 
in  infantilism,  472 
in  late  castrates,  395 
malformations,  385 
in  Mongolism,  496 
in  myxedema,  115 
in  obesity,  574 
in  osteomalacia,  437 
physiology,  371,  374 
in  pregnancy,  378 
pseudohermaphroditism,  387 
sarcoma  of,  427 

transplantation  of,  371,  388,  423 
X-ray  irradiation  of,  371,  427 
glandular  insufficiency,  treatment  of,  422 
Skeleton,  see  osseous  system. 
Sodium  phosphate  in  Basedow's  disease,  102 
Speech  development  in  cretinism,  162 
Spermin,  Poehl,  385,  422 
Squamous-celled  epithelial  carcinoma  of  the 

hypophysis,  321 
Status  lymphaticus,  34,  365 
in  acromegaly,  259 
in  Addison's  disease,  337 
in  Basedow's,  75 
hypoplasticus,  367 
in  thymus  hyperplasia,  226 
Steatoma  of  the  hypophysis,  312 
Stomach  tetany,  214 

treatment  of,  220 
Strabismus  in  tetany,  181 
Struma,  see  goiter. 

hyperplastica  parenchymatosa  teleangi- 

ectodes,  58 
of  the  hypophysis,  269,  312 
Sugar  puncture,  515 

in  animals  without  suprarenals,  344 
without  thyroids,  576 
Suppuration  of  the  suprarenals,  340 
Suprarenal  cortex,  in  acromegaly,  260 
in  Addison's  disease,  361 
aplasia,  350 

in  ductless  glandular  sclerosis,  447 
in  gigantism,  462 
hyperplasia,  351 
hypoplasia,  351 
in  nanisme  type  senile,  351 
physiology,  345 
in  pregnancy,  379 
in  the  premenstrual  period,  375 
in  pseudohermaphroditism,  360 
scleroses,  351 


672 


INDEX 


Suprarenal  cortex,  tumors  of,  356 
hairiness  in,  390 

veins,  thrombosis  of,  340 
Suprarenals,  334 

in  acromegaly,  260 

anatomy,  334 

aplasia,  340 

blood  picture,  337 

blood  sugar,  337 

conditions  of  hyperf unction,  352 

detoxication  theory,  345 

embryology,  334 

in  hemicephaly,  340 

hyperplasia  in  atheromatosis,  355 

in  hypertonia,  354 

implantation  of,  349 

importance  for  life,  342 

in  infections,  341 

leucemia,  348 

loss  of  glycogen  after  extirpation,  349 

in  multiple  ductless  glandular  sclerosis, 

447 

pathological  anatomy,  340 
physiology,  342 

in  progeria,  452 

in  sugar  puncture,  516 

tumors  of  cortex  and  medulla,  363 

see  also  chromaffin  tissue. 
Sympatheticus  in  Addison's  disease,  371 

see  nervous  system. 

tumors  of,  352 
Sympathicotony,  31 

in  Basedow's  disease,  95 
Syphilis  of  the  brain  and  diabetes,  560 

in  ductless  glandular  sclerosis,  448 

in  infantilism,  474 

of  the  pancreas,  520 

of  the  suprarenal  glands,  340 

of  the  thyroid  gland,  55 
Syringomyelia,    differential    diagnosis   from 
acromegaly,  281 

Tabes,  38 

Tachycardia  in  Basedow's,  58 

Teeth  in  acromegaly,  236 

in  myxedema,  105 

see  also  dentition. 
Teratomata  of  the  epiphysis,  330 

of  the  hypophysis,  312 
Testicular  extract,  422 
Tetanoid,  207 
Tetany,  177 

action  of  adrenalin,  183 

in  adipositas  dolorosa,  588 

bladder  symptoms,  192 

blood  picture,  185 


Tetany,  calcium  metabolism,  195 

cardiovascular  apparatus,  184,  185 

cataract,  197 

child  tetanj^  212 

choked  disc  in,  183 

conjunctivitis  in,  198 

definition,  177 

dentition,  197 

differential  diagnosis,  216 

in  ductless  glandular  sclerosis,  499 

eclampsia,  182 

enamel,  defects  of,  197 

epilepsy,  182 

etiology,  208,  210,  211 

forms,  207 

formes  frustes,  216 

in  gastrointestinal  diseases,  214 

gastrointestinal  disturbances,  188 

growth  disturbances  in,  199 

hair  in,  196 

heat  regulation,  192 

idiopathic,  210 

in  infectious  diseases  and  intoxications, 
209 

lachrymation,  184 

magnesium  sulphate  treatment  of,  222 

maternity  tetany,  213 

mental  symptoms,  183 

metabolism,  193 

myotony,  183 

nervous  system,  177 

neuroretinitis,  183 

occupation  tetany,  210 

osteomalacia,  199 

parathyroprivic,  207 

pathogenesis,  200 

pathological  anatomy,  212 

pigmentations,  196 

pilocarpine  action,  183 

prognosis,  218 

pylorospasm,  190 

sensorium,  182 

skin,  196 

spasm  in,  180 

symptomatology,  177 

thermoreaction,  193 

thjToid  gland  in,  200 

in  thyroid  glandular  diseases,  209 

treatment  of,  218,  222 

trophic  disturbances,  196 

vascular  system,  185 
Tetanus,  differential  diagnosis  from  tetany, 
216 

aponicus,  181 
Thermoreaction,  298 
Thorium  treatment,  427 


INDEX 


673 


Thymus  gland,  223 

in  acromegaly,  260 

anatomy,  223 

aplasia,  225 

asthma  thymicum,  228 

blood  picture,  227 

clinical  aspect  of,  225 

in  cretinism,  136 

diseases  of,  223 

in  eunuchoidism,  410 

experimental  physiology,  224 

mors  thy  mica,  227 

status  lymphaticus,  228 

tumors,  228 
hyperplasia,  226 

in  acromegaly,  260 

in  Addison's  disease,  337 

in  Basedow's,  73,  90,  152 

treatment  in  Basedow's,  102 
Thyraden,  140 
Thyreoidinum  siccatum,  140 
Thyroaplasia,  see  also  cretinism,  sporadic. 
Thyroid  elixir,  141 

gland  in  acromegaly,  265 

in  adipositas  dolorosa,  584 

adrenalin     action     after    extirpation, 

343 

anatomy,  53 

in  Basedow's,  58 

in  chlorosis,  430 

in  chondrodystrophy,  493 

in  ductless  glandular  sclerosis,  447 

embryology  of,  53 

effect  on  growth,  15 

in  eunuchoidism,  408 

and  hypophysis,  323 

inflammation,  56 

iodine  contents,  91 

metabolism,  76 

in  obesity,  573 

after  pancreas  extirpation,  506 

in  the  premenstrual  period,  375 

in  pregnancy,  381 

in  tetany,  202 

tumors,  54 
Thyroidin  action  on  nervous  system,  28 
treatment  in  adipositas  dolorosa,  587 

in  athyrosis,  139,  140 

in  cretinism,  143 

combination  with  arsenic,  142 

in  eunuchoidism,  413 

in  hypophysial  dystrophy,  326 

in  sexual  glandular  insufficiency,  422 

in  thyrogenic  obesity,  573 
Thyroidism,  85 


Thyroiditis,  55,  114 
Thyroprivic  equivalents,  119 
Tongue  goiter,  117,  122 
Trauma  in  diabetes,  556 

in  late  eunuchoidism,  414 
Tremor  in  Basedow's,  66 
Trophedema,  585 
Trophoneurosis,  43,  45 
Trousseau's  symptom,  179 
Tryptophan  as  mother-substance  of  pigmen- 
tations in  Addison's  disease,  283 
Typhus      abdominalis,      infantilism      after, 

474 

late  eunuchoidism  after,  418 

thyroiditis  after,  56 
Tubercles  in  floor  of  ventricles,  534 
TubercuUn  injection  in  tetany,  1 82 
Tuberculosis  in  Addison's  disease,  336 

of  the  body  of  the  sphenoid  bone,  325 

in  ductless  glandular  sclerosis,  448 

the  hypophysis,  312 

infantilism,  474 

of  the  parathyroids,  209 

of  the  suprarenals,  340 

of  the  thyroid  gland,  56 

Umbilical  hernia  in  cretinism,  133 

Vagal  neurosis,  38 
Vagotony,  31 

in  Basedow's  disease,  95 

in  status  lymphaticus,  367 

in  thymus  hj^perplasia,  227 
Variola,  thyroiditis  after,  56 
Vascular  system  in  acromegah*,  259 

in  Basedow's  disease,  58 

in  infantilism,  473 

in  myxedema,  106 
Vegetative  disturbances,  464 

nen,'Ous  system,  25 

see  also  nervous  system. 
Voice  in  acromegaly,  237 

in  eunuchoids,  407 

in  late  eunuchoidism,  420 

Water  economy,  20,  38 

in  chlorosis,  430 

in  diabetes  mellitus,  530 
Wave  movement  in  women,  374 

Xanthalasma,  40 

Xanthin  bases,  elimination  in  endemic  cre- 
tinism, 162 
X-ray  examination  in  acromegaly,  237 
in  hypophysial  dystrophy,  311 


674  INDEX 

X-ray  examination,  see  also  epiphysial  junc-  X-ray  treatment  in  acromegah',  282 
tures,  and  osseous  system,  and  growth  in  Basedow's  disease,  loi,  150 

disturbances.  in  chlorosis,  434 

irradiation   of   the   sexual   glands,   371,  in  dysmenorrhea,  434 

427  in  hj'pergenitalism,  427 


RCB48  F19 

1916 


